A biomimetic absorbable filler material and a method of making the same

Abstract

The application provides a kind of bionic absorbable filling material, including the following components by weight parts: 30-50 parts of poly-L-lactic acid, 5-10 parts of polycaprolactone, 2-5 parts of modified hydroxyapatite, 3-6 parts of modified microcrystalline porcelain, 10-20 parts of hyaluronic acid, 3-8 parts of modified chitosan, 4-8 parts of gelatin and 30-50 parts of water.The modified hydroxyapatite is modified by phosphoric acid and silane coupling agent;The modified microcrystalline porcelain is modified by collagen;The diameter of microcrystalline porcelain is 20-40 μm;The modified chitosan is modified by succinic acid;The obtained bionic absorbable filling material has good cell compatibility, moderate mechanical strength and degradation rate, and can meet the clinical application requirements.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of filling materials, and specifically relates to a kind of bionic absorbable filling material and its preparation method. BACKGROUND

[0002] Early research mainly focused on imitating the simple structure and function of natural biological materials, such as collagen and hyaluronic acid. In recent years, with the deepening understanding of the microstructure and function of living organisms, the design of biomimetic materials has become more complex and diverse, capable of simulating multi-scale biological structures and possessing multiple functions.

[0003] 3D printing technology: The application of 3D printing technology enables biomimetic materials to accurately replicate complex three-dimensional structures such as bones, cartilage, and vascular networks. This not only improves the ability of individualized customization of materials, but also provides new possibilities for tissue engineering.

[0004] Nanotechnology: The development of nanotechnology enables biomimetic materials to be designed and manufactured at the nanoscale, resulting in higher specific surface area and better biological activity. For example, nano-hydroxyapatite / polymer composite materials exhibit excellent performance in bone repair.

[0005] Intelligent responsive materials: Intelligent responsive materials that are sensitive to environmental changes (such as pH, temperature, enzyme concentration, etc.) have been developed. These materials can change their properties according to environmental conditions, achieving more precise drug delivery and tissue regeneration.

[0006] Multifunctional integration: By integrating diagnosis, treatment, and monitoring functions into one, biomimetic materials can provide more comprehensive solutions. For example, some materials not only promote tissue regeneration, but also release drugs or carry cells, achieving multiple functions.

[0007] Despite the significant progress made in biomimetic filler materials, there are still some challenges that limit their wider application and development: such as insufficient mechanical strength: the mechanical strength of many biomimetic materials is low, which is difficult to withstand larger loads, especially in the application of load-bearing parts. It is necessary to further improve the mechanical properties of the material to meet the clinical needs; degradation rate regulation: different applications have different requirements for the degradation rate of the material, and too fast or too slow degradation will affect the treatment effect; long-term stability: although biomimetic materials exhibit good biocompatibility and functionality in the short term, their long-term stability and safety still need to be further verified, especially in the case of long-term use in the body environment. There are also immune reactions: although most biomimetic materials have good biocompatibility, they may still trigger immune or inflammatory reactions in some cases. Further research is needed on how to reduce or avoid these adverse reactions. Cell compatibility: some materials may affect cell attachment, proliferation and differentiation, resulting in poor tissue regeneration; it is necessary to optimize the surface properties of the material to improve cell compatibility. SUMMARY

[0008] The purpose of the present application is to provide a preparation method of a biomimetic absorbable filler material, which is obtained by modifying hydroxyapatite, microcrystalline porcelain and chitosan, and adding poly-L-lactic acid, polycaprolactone and hyaluronic acid at the same time; the obtained material has good cell compatibility, moderate mechanical strength and degradation rate, and can meet the clinical application requirements.

[0009] In order to achieve the above purpose, the present application provides the following technical scheme:

[0010] A biomimetic absorbable filler material, comprising the following components in parts by weight: 30-50 parts of poly-L-lactic acid, 5-10 parts of polycaprolactone, 2-5 parts of modified hydroxyapatite, 3-6 parts of modified microcrystalline porcelain, 10-20 parts of hyaluronic acid, 3-8 parts of modified chitosan, 4-8 parts of gelling agent and 30-50 parts of water; the modified hydroxyapatite is modified by phosphoric acid and silane coupling agent; the modified chitosan is modified by succinic acid.

[0011] Further, the molecular weight of the hyaluronic acid is 750-850 thousand Da.

[0012] Further, the molecular weight of the poly-L-lactic acid is 8500-12000.

[0013] A preparation method of a biomimetic absorbable filler material, comprising the following steps:

[0014] S1: preparing modified hydroxyapatite;

[0015] S2: preparing modified chitosan;

[0016] S3: Mix poly-L-lactic acid and poly-caprolactone, raise the temperature to 170-180℃, add modified hydroxyapatite while stirring, keep the temperature for 25-35 min after adding;

[0017] S4: Reduce the temperature to 50-70℃, add hyaluronic acid, modified chitosan, 4-8 parts of gelatin and 30-50 parts of water to step S3, continue stirring for 1-3h, to obtain the biomimetic absorbable filling material.

[0018] Further, step S1 is specifically: according to the solid-liquid ratio of 1g:10-15ml, the nanorod hydroxyapatite is added to the 15-20% phosphoric acid solution, stirred for 10-20min; then 1-3% silane coupling agent is added to the mass of hydroxyapatite, stirred for 30-50min; the temperature is raised to 80-90℃ for reflux reaction for 3-5h; the temperature is reduced to 25-30℃, and the pH value is adjusted to neutral; centrifugal separation, vacuum drying of the solid, to obtain modified hydroxyapatite.

[0019] Further, step S3 is specifically: according to the solid-liquid ratio of 1g:20-30ml chitosan is added to deionized water and mixed uniformly, then 2-3 times the mass of succinic acid is added to the chitosan, stirred at a speed of 600-800r / min for 1-2h; then frozen at minus 35-45℃ for 4-6h to obtain modified chitosan.

[0020] Poly-L-lactic acid (PLLA) is a biodegradable polymer that has been widely used in medical, cosmetic, and tissue engineering fields due to its excellent biocompatibility, mechanical properties, and ability to promote tissue regeneration. PLLA is a linear thermoplastic polymer with a repeating unit of L-lactic acid (L-lactic acid). Its molecular weight can range from a few thousand to hundreds of thousands, depending on the polymerization conditions and application requirements. PLLA has high biocompatibility and complete biodegradability, and does not cause significant immune or toxic reactions in the body. It can be well combined with human tissues and is suitable for long-term implantation. PLLA can be gradually degraded into lactic acid in the body through hydrolysis, and eventually metabolized into carbon dioxide and water, which is excreted from the body. The degradation time is usually 6 months to 2 years, depending on the molecular weight, crystallinity, and application site.

[0021] Poly (caprolactone) is a biodegradable polymer, due to its excellent mechanical properties, good biocompatibility and controllable degradation rate, in the field of medicine, tissue engineering, drug delivery and environment-friendly materials has been widely used. PCL is a linear aliphatic polyester, which is prepared by ring-opening polymerization of epsilon-caprolactone monomer; high biocompatibility: PCL does not cause significant immune response or toxicity in vivo, can be combined with human tissue, suitable for long-term implantation. PCL can be gradually degraded into caprolactone in vivo by hydrolysis, and finally metabolized into carbon dioxide and water, and discharged from the body.

[0022] Hydroxyapatite is an important bioceramic material, due to its excellent biocompatibility and bioactivity, hydroxyapatite can exist in different crystal forms, such as needle-like, flaky, spherical and the like; the crystal form has important influence on its mechanical properties and bioactivity. Hydroxyapatite has very high biocompatibility with human tissue, does not cause significant immune response or toxicity, can be combined with surrounding tissue; the surface of hydroxyapatite can adsorb proteins, growth factors and other biological molecules, promote cell adhesion, proliferation and differentiation, and further enhance its bioactivity.

[0023] Compared with the prior art, the advantages and beneficial effects of the present application are:

[0024] The present application modifies hydroxyapatite with phosphoric acid and silane coupling agent, modifies microcrystalline porcelain with collagen, modifies chitosan with succinic acid, and at the same time under the action of poly-L-lactic acid, polycaprolactone, hyaluronic acid and the like, to prepare a filling material; can provide obvious volume filling effect, and further enhance and prolong the effect by stimulating collagen production; and significantly improve the effect of defect repair, promote new generation, and provide long-term support; promote tissue repair and regeneration, improve the mechanical properties of the filling material, and have good biocompatibility. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0026] The raw materials used in the present application are as follows:

[0027] Hydroxyapatite (Shanghai Yuan Ye Biotechnology Co., Ltd., Item No. S14126); Silane coupling agent (Jiangsu Congzhong Chemical Co., Ltd., Item No. 135); Collagen (Shanghai Yuan Ye Biotechnology Co., Ltd., Item No. S12007); Chitosan (Shanghai Yuan Ye Biotechnology Co., Ltd., Item No. S11064); Succinic acid (Shanghai Yuan Ye Biotechnology Co., Ltd., Item No. S30140); Poly-L-lactic acid (Shanghai Yuan Ye Biotechnology Co., Ltd., Item No. S25218); Hyaluronic acid (Wuhan Fengzhulin Chemical Technology Co., Ltd., Item No. 151).

[0028] Example 1

[0029] The present example provides a preparation method of a biomimetic absorbable filling material, comprising the following steps:

[0030] S1: According to the solid-liquid ratio of 1g:10ml, nanorod hydroxyapatite is added into a 15% mass fraction phosphoric acid solution, stirred at a rate of 500r / min for 10min; then 1% of the mass of hydroxyapatite of silane coupling agent is added, stirred at a rate of 450r / min for 30min; the temperature is raised to 80℃ and refluxed for 3h; the temperature is lowered to 25℃, and the pH value is adjusted to 7; centrifugal separation is performed at 4000r / min for 10min, and the solid is vacuum dried at a pressure of 30mbar and a temperature of 50℃ for 30min to obtain modified hydroxyapatite;

[0031] S2: According to the solid-liquid ratio of 1g:20ml chitosan, chitosan is mixed with deionized water, and then 2 times the mass of chitosan of succinic acid is added, stirred and mixed at a rate of 600r / min for 1h; then frozen at minus 35℃ for 4h to obtain modified chitosan;

[0032] S3: 30g of poly-L-lactic acid and 5g of polycaprolactone are mixed, the temperature is raised to 170℃, 2g of modified hydroxyapatite is added while stirring at a rate of 600r / min, and after the addition is completed, the temperature is maintained for 25min;

[0033] S4: The temperature is lowered to 50℃, 10g of hyaluronic acid and 3g of modified chitosan are added to step S4, and stirring is continued at a rate of 500r / min for 1h to obtain a biomimetic absorbable filling material.

[0034] Example 2

[0035] The present example provides a preparation method of a biomimetic absorbable filling material, comprising the following steps:

[0036] S1: according to the solid-liquid ratio 1g:15ml nanorod-shaped hydroxyapatite is added to the mass fraction 20% phosphoric acid solution, stirring at a rate of 500r / min for 20min; then 3% of the mass of hydroxyapatite silane coupling agent is added, stirring at a rate of 500r / min for 50min; the temperature is raised to 90℃ and refluxed for 5h; the temperature is lowered to 30℃, and the pH value is adjusted to 7; centrifugal separation is performed at 6000r / min for 20min, and the solid is vacuum dried at a pressure of 60mbar and a temperature of 60℃ for 20min to obtain modified hydroxyapatite;

[0037] S2: according to the solid-liquid ratio 1g:30ml chitosan is added to deionized water and mixed uniformly, then 3 times the mass of chitosan succinic acid is added, and stirring is performed at a rate of 800r / min for 2h; then it is frozen at minus 45℃ for 6h to obtain modified chitosan;

[0038] S3: 50g of poly-L-lactic acid and 10g of polycaprolactone are mixed, the temperature is raised to 180℃, 5g of modified hydroxyapatite is added while stirring at a rate of 600r / min, and after the addition is completed, it is kept at temperature for 35min;

[0039] S4: the temperature is lowered to 70℃, 20g of hyaluronic acid and 8g of modified chitosan are added to step S4, and stirring is continued at a rate of 500r / min for 3h to obtain a biomimetic absorbable filling material.

[0040] Example 3

[0041] The embodiment provides a preparation method of a biomimetic absorbable filling material, comprising the following steps:

[0042] S1: according to the solid-liquid ratio 1g:12ml nanorod-shaped hydroxyapatite is added to the mass fraction 18% phosphoric acid solution, stirring at a rate of 500r / min for 15min; then 2% of the mass of hydroxyapatite silane coupling agent is added, stirring at a rate of 600r / min for 45min; the temperature is raised to 85℃ and refluxed for 4.5h; the temperature is lowered to 28℃, and the pH value is adjusted to 7; centrifugal separation is performed at 4500r / min for 25min, and the solid is vacuum dried at a pressure of 45mbar and a temperature of 50℃ for 25min to obtain modified hydroxyapatite;

[0043] S2: according to the solid-liquid ratio 1g:25ml chitosan is added to deionized water and mixed uniformly, then 2.5 times the mass of chitosan succinic acid is added, and stirring is performed at a rate of 700r / min for 1.5h; then it is frozen at minus 40℃ for 5.5h to obtain modified chitosan;

[0044] S3: 45 g of poly-L-lactic acid and 7 g of polycaprolactone were mixed, the temperature was raised to 175℃, 3 g of modified hydroxyapatite was added while stirring at a rate of 500 r / min, and after the addition was completed, it was kept for 30 min;

[0045] S4: the temperature was lowered to 65℃, 15 g of hyaluronic acid and 6 g of modified chitosan were added to step S4, and stirring was continued at a rate of 500 r / min for 2.5 h to obtain a biomimetic absorbable filling material.

[0046] Comparative Example 1

[0047] The difference from Example 1 is that modified hydroxyapatite is not used in step S1, and hydroxyapatite is directly used, and the other steps are unchanged.

[0048] Comparative Example 2

[0049] The difference from Example 1 is that chitosan is used in step S3, and it is not modified, and the other steps are unchanged.

[0050] Comparative Example 3

[0051] The difference from Example 1 is that modified hydroxyapatite is not added in step S4, and the other steps are unchanged.

[0052] Comparative Example 4

[0053] The difference from Example 1 is that modified chitosan is not added in step S5, and the other steps are unchanged.

[0054] Performance test: the biomimetic absorbable filling material obtained in each example and comparative example was prepared into a sample, and was cut into a standard dumbbell-shaped sample with a length of 50 mm, a width of 4 mm, and a thickness of 0.5 mm, and the tensile gauge length was 20 mm; an electronic universal testing machine was used to test the mechanical properties, and the elastic recovery of each sample was tested. The test temperature was room temperature, and the tensile rate was 200 mm / min; the tensile strength, elongation at break, shrinkage rate, and elastic recovery rate were tested.

[0055]

[0056] From the above performance test results, it can be seen that the absorbable filling materials prepared in Examples 1-3 have good mechanical properties and good biocompatibility. In particular, Example 3 has better comprehensive performance. However, Comparative Examples 1-5 do not use the necessary technical solutions, resulting in a significant difference in the corresponding performance tests compared to the examples. The above experimental results further prove the importance of the technical solutions defined in the present application for its technical effects.

[0057] The above is the preferred embodiment of the present application, it should be noted that for those skilled in the art, without departing from the principles described in the present application, can also make several improvements and refinements, these improvements and refinements should also be considered as the scope of protection of the present application.

Claims

1. A biomimetic absorbable filler material, characterized in that, The components include the following by weight parts: 30-50 parts of poly-L-lactic acid, 5-10 parts of polycaprolactone, 2-5 parts of modified hydroxyapatite, 3-6 parts of modified microcrystalline porcelain, 10-20 parts of hyaluronic acid, 3-8 parts of modified chitosan, 4-8 parts of gelling agent and 30-50 parts of water; the modified hydroxyapatite is modified by phosphoric acid and silane coupling agent; the modified chitosan is modified by succinic acid; the modified microcrystalline porcelain is modified by collagen; the diameter of the microcrystalline porcelain is 20-40 μm.

2. The biomimetic resorbable filler material of claim 1, wherein, The molecular weight of the hyaluronic acid is 750-850 thousand Da.

3. The bioresorbable filler material of claim 1, wherein, The molecular weight of the poly-L-lactic acid is 8500-12000.

4. A method of preparing a biomimetic absorbable filler material, characterized by, The steps include the following: S1: preparing modified hydroxyapatite; S2: preparing modified microcrystalline porcelain; S3: preparing modified chitosan; S4: mixing poly-L-lactic acid and polycaprolactone, increasing the temperature to 170-180℃, adding the modified hydroxyapatite and modified microcrystalline porcelain while stirring, and keeping the temperature for 25-35 min after the addition is completed; S5: reducing the temperature to 50-70℃, adding hyaluronic acid, modified chitosan, gelling agent and water to step S4, and continuing to stir for 1-3 h to obtain a biomimetic absorbable filling material; step S1 specifically includes: adding nanorod hydroxyapatite into a 15-20% phosphoric acid solution according to a solid-liquid ratio of 1g:10-15 ml, stirring for 10-20 min; then adding 1-3% silane coupling agent based on the mass of the hydroxyapatite, stirring for 30-50 min; increasing the temperature to 80-90℃ for reflux reaction for 3-5 h; reducing the temperature to 25-30℃, and adjusting the pH value to neutral; After centrifugal separation, the solid is vacuum dried to obtain the modified hydroxyapatite.

5. The method for preparing a biomimetic absorbable filler material according to claim 4, characterized in that, Step S2 specifically includes: adding 2-3 parts of collagen into 20-30 parts of microcrystalline porcelain, ultrasonic dispersing at a temperature of 45-55℃ and a power of 500-700 W for 40-60 min to obtain the modified microcrystalline porcelain.

6. The method for preparing a biomimetic absorbable filler material according to claim 4, characterized in that, Step S3 specifically includes: mixing chitosan with deionized water according to a solid-liquid ratio of 1g:20-30 ml, then adding 2-3 times the mass of the chitosan of succinic acid, stirring and mixing at a speed of 600-800 r / min for 1-2 h; then freezing at minus 35-45℃ for 4-6 h to obtain the modified chitosan.

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