Collagen composite artificial bone and preparation method thereof

Abstract

The invention discloses a collagen composite artificial bone which is characterized in that raw materials comprise type I collagen and hydroxyapatite, and further comprise one or more of polylactic acid, polyglycolic acid, a polylactic acid-glycolic acid copolymer, polycaprolactone, poly (trimethylene carbonate), polymethyl methacrylate, hyaluronic acid and alginic acid. According to the collagen composite artificial bone, one or more specific high polymer materials are added in the preparation process of the artificial bone, so that the collagen composite artificial bone has excellent mechanical properties and stability, and the preparation method is simple, easy in expanded production, high in yield and low in cost. The artificial bone is suitable for various application fields such as various bone fractures with bone defects, nonunion or deformity healing, orthopedic bone grafting, other bone defect repair without bone grafting taboo in the orthopedics department and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical biomaterials, and in particular relates to enhancing the compressive strength and porosity of artificial bones by adding hydroxyapatite and other polymer materials, and specifically relates to a collagen composite artificial bone and a preparation method thereof. Background Art

[0002] Bone defects and fractures are common clinical presentations for surgeons. With an aging population and increased life expectancy, these cases are expected to increase. Traditional methods used to treat these clinical problems have their limitations: autologous bone transplants are susceptible to donor availability; allogeneic bone transplants carry the risk of rejection and are relatively expensive; and artificial bones made from polymers, ceramics, or titanium alloys offer unsatisfactory long-term results.

[0003] Collagen-composite artificial bone is a biomedical material that mimics the structure and composition of natural bone. Composed primarily of collagen and bioceramics such as hydroxyapatite, it exhibits excellent biocompatibility, bioactivity, and biodegradability. Its main components are type I collagen as the primary organic component and hydroxyapatite and other bioceramics as inorganic components. Type I collagen is the primary organic component of natural bone, accounting for approximately 34% of bone mass, while hydroxyapatite is the primary inorganic component of natural bone, making up approximately 65% of bone mass. Structurally, it possesses a three-dimensional interconnected porous structure, similar to the microstructure of natural bone, which facilitates the adhesion, proliferation, and differentiation of osteoblasts, as well as the migration and transport of nutrients.

[0004] Although collagen composite artificial bone has the above-mentioned obvious advantages, there is still much room for improvement in its mechanical properties such as compressive strength and porosity. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to enhance the mechanical properties of collagen composite artificial bone, especially the compressive strength performance and porosity. The purpose of the present invention is to prepare a collagen composite artificial bone, which is suitable for various types of fractures with bone defects; bone nonunion or malunion and orthopedic bone grafting; intervertebral, intertransverse process or interlaminar bone grafting fusion; bone defect repair after resection of benign bone tumors or tumor-like lesions; and other types of bone defect repair in orthopedics without bone grafting contraindications. The collagen composite artificial bone has excellent biological activity, bone conductivity, outstanding mechanical properties and stability. When used for bone tissue repair, its porosity is conducive to the migration and transmission of osteoblasts and nutrients, promotes new bone formation, and over time, the artificial bone will gradually degrade and be absorbed and replaced by new bone.

[0006] In order to solve the above technical problems, the specific technical solutions adopted by the present invention are as follows:

[0007] In the first aspect of the present invention, a collagen composite artificial bone is provided, characterized in that the raw materials include type I collagen, hydroxyapatite, and also include one or more polymer materials selected from polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polytrimethylene carbonate, polymethyl methacrylate, hyaluronic acid, alginate, etc.

[0008] In some specific embodiments, the raw materials include type I collagen, hydroxyapatite, polymethyl methacrylate, and alginic acid.

[0009] In some specific embodiments, the raw materials include type I collagen, hydroxyapatite, hyaluronic acid, and alginate.

[0010] In some specific embodiments, the raw materials include type I collagen, hydroxyapatite, polymethyl methacrylate, hyaluronic acid, and alginate.

[0011] In a second aspect of the present invention, a method for preparing a collagen-composite artificial bone is provided, characterized in that the method comprises the following steps:

[0012] S1, collagen pre-frozen;

[0013] S2. Pre-frozen collagen, hydroxyapatite, polymer material, and water are mixed in a certain proportion to form a slurry;

[0014] S3, the mixed slurry is injected into the mold and pressed into shape;

[0015] S4, pre-freeze the slurry in the mold under low temperature conditions;

[0016] S5. Freeze-drying the demoulding slurry to obtain the collagen composite artificial bone.

[0017] The collagen is type I collagen, and the polymer material is selected from one or more of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polytrimethylene carbonate, polymethyl methacrylate, hyaluronic acid, and alginic acid.

[0018] In some specific embodiments, step S2 further comprises first crushing the pre-frozen collagen to a particle size of no more than 1 mm, and then mixing it with other ingredients.

[0019] In some specific embodiments, step S2 is to mix collagen and water in proportion to obtain a uniform milky white particle-free solution, and then add the polymer material and hydroxyapatite and mix them evenly.

[0020] In some specific embodiments, the ratio of the collagen to water is 1.5-10:1.5-7.5, the ratio of the collagen to the polymer material is 1.5-0.05:1.5-0.1, and the ratio of the collagen to the hydroxyapatite is 1.5-1:1.5-1.5.

[0021] In some specific embodiments, the low temperature condition in step S4 is -20 to -50°C, and the pre-freezing time is 6 to 10 hours.

[0022] In some specific embodiments, the preparation method is characterized by comprising the following steps:

[0023] S1. freeze-drying the collagen according to a predetermined procedure;

[0024] S2. Chop the pre-frozen collagen into pieces to a particle size of no more than 1 mm, mix the chopped collagen and water in proportion to obtain a uniform milky white particle-free solution, and then add the polymer material and hydroxyapatite and mix; the ratio of the collagen to water is 1.5-10:1.5-7.5, the ratio of the collagen to the polymer material is 1.5-0.05:1.5-0.1, and the ratio of the collagen to the hydroxyapatite is 1.5-1:1.5-1.5.

[0025] S3, injecting the mixed slurry into the mold, compacting it, and pre-molding it;

[0026] S4. Pre-freeze the mold containing the slurry at -20°C for 6 hours;

[0027] S5. After the pre-frozen slurry is demoulded, it is placed in a freeze-drying tray; a freeze dryer is turned on, and the freeze-drying tray is placed in the freeze dryer for freeze drying. After freeze drying, the collagen composite artificial bone is obtained.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] By adding one or more specific polymer materials during the artificial bone preparation process, the present invention achieves excellent mechanical properties and stability in this collagen-composite artificial bone. Furthermore, the preparation method is simple, easily scalable, and has high yield and low cost. This artificial bone is suitable for a wide range of applications, including various fractures with bone defects, nonunions or malunions, orthopedic bone grafting, and other orthopedic bone defect repair procedures where bone grafting is not contraindicated.

[0030] The concept of the present invention and the technical effects produced will be further described below to fully understand the purpose, characteristics and effects of the present invention. DETAILED DESCRIPTION

[0031] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the invention is further described below. However, the invention is not limited to the following implementation cases.

[0032] It should be noted that this specification is intended for understanding and reading by persons familiar with this technology and is not intended to limit the conditions under which the present invention can be implemented. Therefore, it has no substantive technical significance. Any structural modification, change in proportional relationship, or adjustment in size should still fall within the scope of the technical content disclosed in the present invention without affecting the efficacy and purpose of the present invention.

[0033] All materials involved in the examples are commercially available products.

[0034] Hydroxyapatite was purchased from Zhejiang Apre Nano New Materials Co., Ltd.; polylactic acid was purchased from Shanghai Huawuhan Haishan Technology Co., Ltd., with a molecular weight of 10,000-1,000,000; polyglycolic acid was purchased from Beijing Biolab Technology Co., Ltd., with a molecular weight of 10,000-20,000; polylactic acid-glycolic acid copolymer was purchased from Shenzhen Green Protection Biotechnology Co., Ltd., with a molecular weight of more than 30,000; polycaprolactone was purchased from Shanghai Saikrui Biotechnology Co., Ltd., with a molecular weight of 150,000; polytrimethylene carbonate was purchased from Shenzhen Boli Biomaterials Co., Ltd., with a molecular weight of 477,000-579,000; polymethyl methacrylate was purchased from Shanghai Huayuan Century Trading Co., Ltd.; hyaluronic acid was purchased from Avituo (Shanghai) Pharmaceutical Technology Co., Ltd., with a molecular weight of 600,000-1.2 million; and alginic acid was purchased from Shanghai Huayuan Century Trading Co., Ltd. Compressive strength test method:

[0035] With reference to "YY / T 1558.3-2017 Calcium Phosphates for Surgical Implants Part 3: Hydroxyapatite and β-tricalcium phosphate Bone Substitutes", the mechanical strength of block bone substitutes should be measured by a compressive strength test, and the compressive strength test shown in "Figure 2 Schematic Diagram of Compressive Strength Test" in "4.6 Measurement of Mechanical Strength of Materials" on page 6 of the above standard should be used for measurement.

[0036] Porosity detection method:

[0037] Use a 50ml pycnometer, at a constant temperature of 30℃, select a pycnometer filled with ethanol solution, immerse the sample in ethanol to degas, so that the ethanol fills the sample, then fill it with ethanol, take out the sample soaked in ethanol and calculate the porosity of the sample according to the formula.

[0038] Volume of sample: VR = (m1-m2+m0) / ρ

[0039] The volume of the pores inside the sample: VP = (m2-m3-m0) / ρ

[0040] Sample porosity: q = [VP / (VP+VR)]*100% = [(m2-m3-m0) / (m1-m3)]*100% Sample bulk density: d = m0 / (VR+VP) = m0*ρ / (m1-m3)

[0041] m1: the weight of the pycnometer filled with ethanol solution;

[0042] m2: The weight of the entire pycnometer after the sample is immersed in ethanol for degassing and then filled with ethanol;

[0043] m3: The weight of the remaining ethanol and the pycnometer after the sample soaked in ethanol is taken out;

[0044] m0: dry weight of the sample;

[0045] ρ: density of ethanol at the measurement temperature.

[0046] The test was carried out according to the above method.

[0047] Comparative Example

[0048] The preparation method of type I collagen composite artificial bone comprises the following steps:

[0049] (1) Type I collagen was freeze-dried according to a predetermined procedure: the freeze-drying plate temperature was -20°C, and after reaching -20°C, the temperature was kept for 4 hours, and then the temperature was increased at a rate of 10°C every 4 hours until the temperature reached 20°C. The entire heating process took 16 hours. The temperature was then kept at 25°C for 8 hours and freeze-dried.

[0050] (2) Chop the pre-frozen type I collagen into small pieces to a particle size of no more than 1 mm, mix 1.5 g of the chopped type I collagen with 7.5 g of water to obtain a uniform milky white solution without particles, and then add 1 g of hydroxyapatite and mix to form a slurry.

[0051] (3) Pour the mixed slurry into the mold, compact it, and pre-mold it.

[0052] (4) Place the mold containing the slurry at -20℃ for pre-freezing for 6 hours.

[0053] (5) After the pre-frozen slurry is demoulded, it is placed in a freeze-drying tray; the freeze dryer is turned on, and the freeze-drying tray is placed in the freeze dryer for freeze drying. After freeze drying, the collagen composite artificial bone is obtained.

[0054] Example 1

[0055] The preparation method of type I collagen composite artificial bone comprises the following steps:

[0056] (1) Type I collagen was freeze-dried according to a predetermined procedure: the freeze-drying plate temperature was -20°C, and after reaching -20°C, the temperature was kept for 4 hours, and then the temperature was increased at a rate of 10°C every 4 hours until the temperature reached 20°C. The entire heating process took 16 hours. The temperature was then kept at 25°C for 8 hours and freeze-dried.

[0057] (2) Chop the pre-frozen type I collagen into small pieces to a particle size of no more than 1 mm. Mix 1.5 g of the chopped type I collagen with 7.5 g of water to obtain a uniform milky white solution without particles. Then add 0.1 g of polylactic acid and 1 g of hydroxyapatite and mix well to form a slurry.

[0058] (3) Pour the mixed slurry into the mold, compact it, and pre-mold it.

[0059] (4) Place the mold containing the slurry at -20℃ for pre-freezing for 6 hours.

[0060] (5) After the pre-frozen slurry is demoulded, it is placed in a freeze-drying tray; the freeze dryer is turned on, and the freeze-drying tray is placed in the freeze dryer for freeze drying. After freeze drying, the collagen composite artificial bone is obtained.

[0061] Example 2

[0062] In step (2), 1.5 g of type I collagen, 7.5 g of water, 0.1 g of polyglycolic acid, and 1 g of hydroxyapatite were added and mixed to form a slurry. The other steps were the same as those in Example 1.

[0063] Example 3

[0064] In step (2), 1.5 g of type I collagen, 7.5 g of water, 0.1 g of poly(lactic acid-co-glycolic acid) copolymer, and 1 g of hydroxyapatite were added and mixed to form a slurry. The other steps were the same as those in Example 1.

[0065] Example 4

[0066] In step (2), 1.5 g of type I collagen, 7.5 g of water, 0.1 g of polycaprolactone, and 1 g of hydroxyapatite were added and mixed to form a slurry. The other steps were the same as those in Example 1.

[0067] Example 5

[0068] In step (2), 1.5 g of type I collagen, 7.5 g of water, 0.1 g of polytrimethylene carbonate, and 1 g of hydroxyapatite were added and mixed to form a slurry. The other steps were the same as those in Example 1.

[0069] Example 6

[0070] In step (2), 1.5 g of type I collagen, 7.5 g of water, 0.1 g of polymethyl methacrylate, and 1 g of hydroxyapatite were added and mixed to form a slurry. The other steps were the same as those in Example 1.

[0071] Example 7

[0072] In step (2), 1.5 g of type I collagen, 7.5 g of water, 0.1 g of hyaluronic acid, and 1 g of hydroxyapatite were added and mixed to form a slurry. The other steps were the same as those in Example 1.

[0073] Example 8

[0074] In step (2), 1.5 g type I collagen, 7.5 g water, 0.1 g alginic acid, and 1 g hydroxyapatite were added and mixed to form a slurry. The other steps were the same as in Example 1.

[0075] Example 9

[0076] In step (2), 1.5 g of type I collagen, 10 g of water, 0.05 g of polymethyl methacrylate, 0.05 g of hyaluronic acid, and 1.5 g of hydroxyapatite were added and mixed to form a slurry. The other steps were the same as those in Example 1.

[0077] Example 10

[0078] In step (2), 1.5 g type I collagen, 7.5 g water, 0.05 g polymethyl methacrylate, 0.05 g alginic acid, and 1 g hydroxyapatite were added and mixed to form a slurry. The other steps were the same as in Example 1.

[0079] Example 11

[0080] In step (2), 1.5 g type I collagen, 7.5 g water, 0.05 g hyaluronic acid, 0.05 g alginic acid, and 1 g hydroxyapatite were added and mixed to form a slurry. The other steps were the same as in Example 1.

[0081] Example 12

[0082] In step (2), 1.5 g type I collagen, 7.5 g water, 0.025 g polymethyl methacrylate, 0.025 g hyaluronic acid, 0.05 g alginic acid, and 1 g hydroxyapatite were added and mixed to form a slurry. The other steps were the same as in Example 1.

[0083] Example 13

[0084] In step (2), 1.5 g type I collagen, 7.5 g water, 0.05 g alginic acid, and 1 g hydroxyapatite were added and mixed to form a slurry. The other steps were the same as in Example 1.

[0085] The experimental results of the above comparative examples and embodiments 1 to 12 are summarized in Table 1.

[0086] Table 1 Experimental results

[0087]

[0088]

[0089] From the above experimental results, it can be seen that in the preparation process of type I collagen composite artificial bone, adding polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polytrimethylene carbonate, polymethyl methacrylate, hyaluronic acid, alginic acid or adding a combination of polymethyl methacrylate and hyaluronic acid, or adding a combination of polymethyl methacrylate and alginic acid, or adding a combination of hyaluronic acid and alginic acid, or adding a combination of polymethyl methacrylate, hyaluronic acid, and alginic acid can improve the compressive strength and porosity of the product.

[0090] The preferred embodiments of the present invention have been described in detail above. It should be understood that numerous modifications and variations based on the concepts of the present invention are possible without inventive effort by those skilled in the art. Therefore, any technical solution that can be derived by one skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. A collagen composite artificial bone, characterized in that: The raw materials include type I collagen, hydroxyapatite, and one or more selected from polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polytrimethylene carbonate, polymethyl methacrylate, hyaluronic acid, and alginic acid.

2. The collagen composite artificial bone according to claim 1, characterized in that: The raw materials include type I collagen, hydroxyapatite, polymethyl methacrylate and alginic acid.

3. The collagen composite artificial bone according to claim 1, characterized in that: The raw materials include type I collagen, hydroxyapatite, hyaluronic acid and alginate.

4. The collagen composite artificial bone according to claim 1, characterized in that: The raw materials include type I collagen, hydroxyapatite, polymethyl methacrylate, hyaluronic acid and alginate.

5. A method for preparing collagen-composite artificial bone, characterized in that: The following steps are involved: S1, collagen pre-frozen; S2. Pre-frozen collagen, hydroxyapatite, polymer material, and water are mixed in a certain proportion to form a slurry; S3, the mixed slurry is injected into the mold and pressed into shape; S4, pre-freeze the slurry in the mold under low temperature conditions; S5. Freeze-drying the demoulding slurry to obtain the collagen composite artificial bone. The collagen is type I collagen, and the polymer material is selected from one or more of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polytrimethylene carbonate, polymethyl methacrylate, hyaluronic acid, and alginic acid.

6. The method for preparing collagen composite artificial bone according to claim 5, characterized in that: The step S2 further includes first crushing the pre-frozen collagen into particles no larger than 1 mm, and then mixing with other ingredients.

7. The method for preparing collagen composite artificial bone according to claim 6, characterized in that: The step S2 is to mix the collagen and water in proportion to obtain a uniform milky white solution without particles, and then add the polymer material and hydroxyapatite to mix.

8. The method for preparing collagen composite artificial bone according to any one of claims 5 to 7, characterized in that: The ratio of the collagen to water is 1.5-10:1.5-7.5, the ratio of the collagen to the polymer material is 1.5-0.05:1.5-0.1, and the ratio of the collagen to the hydroxyapatite is 1.5-1:1.5-1.

5.

9. The method for preparing collagen composite artificial bone according to claim 5, characterized in that: The low temperature condition in step S4 is -20 to -50°C, and the pre-freezing time is 6 to 10 hours.

10. The method for preparing collagen composite artificial bone according to claim 5, characterized in that: The following steps are involved: S1. freeze-drying the collagen according to a predetermined procedure; S2. Chop the pre-frozen collagen into pieces to a particle size of no more than 1 mm, mix the chopped collagen and water in proportion to obtain a uniform milky white particle-free solution, and then add the polymer material and hydroxyapatite and mix to form a slurry; the ratio of the collagen to water is 1.5-10:1.5-7.5, the ratio of the collagen to the polymer material is 1.5-0.05:1.5-0.1, and the ratio of the collagen to the hydroxyapatite is 1.5-1:1.5-1.5; S3, injecting the mixed slurry into the mold, compacting it, and pre-molding it; S4. Pre-freeze the mold containing the slurry at -20°C for 6 hours; S5. After the pre-frozen slurry is demoulded, it is placed in a freeze-drying tray; a freeze dryer is turned on, and the freeze-drying tray is placed in the freeze dryer for freeze drying. After freeze drying, the collagen composite artificial bone is obtained.

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