Artificial bone scaffold material for 3D printing and preparation method and application thereof

文档序号：623719 发布日期：2021-05-11 浏览：3次中文

阅读说明：本技术 一种3d打印用人工骨支架材料及其制备方法和应用 (Artificial bone scaffold material for 3D printing and preparation method and application thereof ) 是由刘辉林唐京科陈春敖丹军蔡君威于 2021-01-26 设计创作，主要内容包括：本发明涉及一种3D打印用人工骨支架材料及其制备方法和应用,所述3D打印用人工骨支架材料包括可降解高分子材料、生物活性陶瓷和量子点。该3D打印用人工骨支架材料把无机材料的刚性、强度和骨传导性与高分子材料的强度、生物降解性以及量子点稳定的荧光效应有效地结合了起来,三者协同配合作用,其在机械强度上比单纯的高分子材料或生物活性陶瓷有显著的提升,其硬度、韧性等生物力学方面均更有优势。量子点的加入赋予骨支架材料在荧光下显影降解速率可监控的功能,可用于骨材料内化吸收的跟踪。生物活性陶瓷能将内部的量子点更好地与生理环境隔绝开,保证了量子点的性能稳定,且量子点会逐渐降解得到缓慢释放,进而被安全地代谢出体外。(The invention relates to an artificial bone scaffold material for 3D printing, and a preparation method and application thereof. The artificial bone scaffold material for 3D printing effectively combines the rigidity, strength and osteoconductivity of inorganic materials with the strength, biodegradability of high polymer materials and the stable fluorescence effect of quantum dots, and the three materials are cooperated to act, so that the mechanical strength of the artificial bone scaffold material is remarkably improved compared with that of a pure high polymer material or bioactive ceramics, and the artificial bone scaffold material has more advantages in the aspects of biomechanics such as hardness and toughness. The addition of the quantum dots endows the bone scaffold material with a function of monitoring the development degradation rate under fluorescence, and can be used for tracking the internalization and absorption of the bone material. The bioactive ceramic can better isolate the internal quantum dots from the physiological environment, ensures the stable performance of the quantum dots, and gradually degrades the quantum dots to be slowly released so as to be safely metabolized out of the body.)

1. The 3D printing artificial bone scaffold material is characterized by comprising a degradable high polymer material, bioactive ceramics and quantum dots.

2. The artificial bone scaffold material for 3D printing according to claim 1, wherein the artificial bone scaffold material for 3D printing comprises 50-90% of degradable high polymer material, 5-50% of bioactive ceramic and 0.5-5% of quantum dots in percentage by weight.

3. The artificial bone scaffold material for 3D printing according to claim 1 or 2, wherein the degradable high polymer material is selected from one or a combination of at least two of polyglycolide, polylactide, polylactic acid-glycolic acid copolymer, polycaprolactone or polyhydroxyalkanoate;

preferably, the degradable high molecular material is selected from the combination of polylactide and polycaprolactone;

preferably, the mass ratio of the polylactide to the polycaprolactone is (3-5): 1.

4. The artificial bone scaffold material for 3D printing according to any one of claims 1 to 3, wherein the bioactive ceramic is selected from any one of calcium phosphate ceramic, calcium silicate ceramic or bioactive glass or a combination of at least two thereof; preferably a combination of calcium phosphate ceramic and calcium silicate ceramic;

preferably, the calcium phosphate ceramic comprises any one of hydroxyapatite, β -tricalcium phosphate or biphasic calcium phosphate, or a combination of at least two thereof;

preferably, the calcium silicate ceramic comprises any one of calcium silicate, dicalcium silicate, tricalcium silicate, diopside, akermanite or whitlaite, or a combination of at least two thereof;

preferably, the bioactive glass is a silicate glass containing silicon oxide, sodium oxide, calcium oxide and phosphorus oxide.

5. The artificial bone scaffold material for 3D printing according to any one of claims 1 to 3, wherein the bioactive ceramic is selected from the group consisting of hydroxyapatite and calcium silicate;

preferably, the mass ratio of the hydroxyapatite to the calcium silicate is 1:3-3: 1;

preferably, the bioactive ceramic has a particle size of 50nm to 10 μm.

6. The artificial bone scaffolding material for 3D printing according to any one of claims 1-5, characterized in that the quantum dots are selected from any one or a combination of at least two of CdTe, CdS, CdSe, ZnSe, ZnO, CdSe/ZnS, CdSe/CdS or CdS/ZnS;

preferably, the particle size of the quantum dots is 2-20 nm;

preferably, the surface of the quantum dot is modified with a functional modifier.

7. The preparation method of the artificial bone scaffold material for 3D printing according to any one of claims 1 to 6, wherein the preparation method comprises the following steps:

(1) mixing the degradable high polymer material with an organic solvent, then mixing with a quantum dot solution, distilling the mixed solution and then drying to obtain a degradable high polymer/quantum dot composite material;

(2) blending, extruding and granulating the degradable polymer/quantum dot composite material obtained in the step (1), and drying to obtain degradable polymer/quantum dot composite material granules;

(3) blending, extruding and granulating the degradable polymer/quantum dot composite material granules obtained in the step (2) and bioactive ceramics, and drying to obtain composite material granules;

(4) and (4) extruding, drawing and drying the composite material granules obtained in the step (3) to obtain the artificial bone scaffold material for 3D printing.

8. The method for preparing an artificial bone scaffold material for 3D printing according to claim 7, wherein the organic solvent in step (1) comprises any one or a combination of at least two of dichloromethane, chloroform, tetrahydrofuran, acetone or ethyl acetate;

preferably, the degradable high molecular material in the step (1) is 2-8% by mass in the organic solvent;

preferably, the mass percentage of the quantum dots in the degradable polymer/quantum dot composite material in the step (1) is 0.5-5%.

9. The method for preparing the artificial bone scaffold material for 3D printing according to claim 7 or 8, wherein the diameter of the artificial bone scaffold material for 3D printing in the step (4) is 1.5-2 mm.

10. Use of the artificial bone scaffold material for 3D printing according to any one of claims 1 to 6 for preparing an artificial bone.

Technical Field

The invention belongs to the technical field of orthopedic 3D printing, and particularly relates to an artificial bone scaffold material for 3D printing, a preparation method and application thereof, and in particular relates to a biodegradable artificial bone scaffold material for 3D printing, which is good in mechanical property, and a preparation method and application thereof.

Background

The skeleton provides skeleton for human body, supports weight and motion of human body, protects vital organs. The primary bone tumor has a low incidence, but solid tumors are easily transferred to bone tissues (such as prostate cancer, breast cancer, lung cancer, kidney cancer, etc.) due to the special environment of bones. In patients with tumor skeletal metastases, the decline in quality of life and eventual death is almost entirely caused by complications such as bone pain, hypercalcemia, pathological fractures, and dural compression. For the treatment of bone tumors, the main purposes are to relieve pain, prevent pathological fractures, improve mobility and function and prolong life span. The current surgical strategy is to refine the range of resection and protect healthy tissues by assisting imaging technology and preoperative chemotherapy. The surgical resection is followed by filling and treatment with a filling synthetic bone repair material.

The biological materials used for bone repair at present are medical metal materials, medical high polymer materials, medical biological ceramic materials and medical composite materials. A great deal of research at home and abroad finds a plurality of potential materials which can be used for preparing the artificial bone, but most of the potential materials focus on a single material or only research on a certain characteristic to obtain a certain effect, but the clinical satisfactory bone defect repairing effect cannot be achieved. When the medical metal implant material is used as an internal fixation material, the medical metal implant material is ideal in strength and biocompatibility, but the application process of the medical metal implant material still has more complications, such as corrosion damage of a metal implant, metal anaphylaxis, stress shielding effect and osteoporosis, and the internal fixation material needs to be taken out through a secondary operation, so that a great burden is brought to a patient on spirit and substances.

In order to overcome the defect of using metal internal fixation materials during fracture, the absorbable internal fixation materials are researched from 20 th century 60 s abroad, generally, the absorbable materials are artificially synthesized high molecular organic matters or natural high molecular materials, and after hydrolysis and oxidation reactions in vivo, the final metabolites are discharged out of the body through a respiratory system or a urinary system, do not accumulate in the body, have almost no toxic effect, and do not need to be taken out through a secondary operation. Common absorbable materials are Polyglycolide (PGA), Polylactide (PLA), polylactic-co-glycolic acid (PLGA), and the like.

The biological ceramic material includes two main types of biological inert ceramics and biological active ceramics. The biological inert ceramics mainly comprise zinc oxide, aluminum oxide, zirconium oxide, silicon carbide and the like, and the biological inert ceramics are often used as implant surface modification materials. The bioactive ceramics mainly comprise calcium phosphate ceramics, calcium silicate ceramics, bioactive glass ceramics and the like. The pure bioactive ceramic material has high brittleness and low strength, and cannot meet the load bearing requirement of the artificial bone. The long-term clinical practice shows that the components of the material, whether the material is a metal material or an organic polymer material, are greatly different from natural bones, and the material is not satisfactory in biocompatibility, human body adaptability and mechanical compatibility among natural bones as a substitute material of the bones.

At present, there are some prior arts that a phosphor is mixed with a polymer colloid in a certain ratio to prepare a polymer colloid doped with the phosphor, and the polymer colloid doped with the phosphor is printed by a nozzle. However, the polymer colloid doped with the phosphor has the following problems: 1) the fluorescent powder has larger particles, and the fluorescent powder is easy to precipitate and cause agglomeration when being mixed with the polymer colloid, so that the fluorescent powder is unevenly distributed in the polymer colloid; 2) because the difference between the refractive indexes of the fluorescent powder and the polymer colloid is large, a strong light scattering effect can be formed on the contact surface of the fluorescent powder and the polymer colloid. 3) Organic matters in the polymer colloid doped with the fluorescent powder and the inorganic fluorescent powder are subjected to chemical reaction, so that the emission spectrum of the fluorescent powder is changed. Therefore, the development of phosphor paste in the field of 3D printing is limited.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide an artificial bone scaffold material for 3D printing and a preparation method and application thereof, and particularly provides a biodegradable artificial bone scaffold material for 3D printing with good mechanical property and a preparation method and application thereof

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the invention provides an artificial bone scaffold material for 3D printing, which comprises a degradable high polymer material, bioactive ceramics and quantum dots.

The artificial bone scaffold material for 3D printing, which is disclosed by the invention, is prepared by compounding degradable high polymer material, bioactive ceramic and quantum dots, effectively combining the rigidity, strength and bone conductivity of inorganic material with the strength, biodegradability and stable fluorescence effect of the quantum dots of the high polymer material, and realizing the synergistic cooperation of the three materials, so that the mechanical strength of the artificial bone scaffold material is remarkably improved compared with that of the pure high polymer material or bioactive ceramic, and the artificial bone scaffold material has the advantages of hardness, toughness and other biomechanics. Meanwhile, the degradation product of the bioactive ceramic is alkaline, so that the bioactive ceramic can be used for neutralizing high-molecular acidic degradation products, and the effects of delaying degradation speed and improving material bioactivity and biocompatibility are achieved. The addition of the quantum dots endows the bone scaffold material with a function of monitoring the development degradation rate under fluorescence, can be used for tracking the internalization absorption of the bone material, and compared with the existing fluorescent powder doping technology, the quantum dot fluorescent probe has the advantages of small scattering in the composite material, uniform dispersion and no agglomeration and precipitation phenomena; the quantum dots have longer service life than fluorescent dye, wide and continuous distribution of excitation spectrum, narrow and symmetrical emission spectrum, adjustable color and high photochemical stability, are more ideal fluorescent probe materials and are easy to obtain fluorescent signals without background interference; the bioactive ceramic can better isolate the internal quantum dots from the physiological environment, ensures the stable performance of the quantum dots, and gradually degrades the quantum dots to be slowly released so as to be safely metabolized out of the body.

Preferably, the artificial bone scaffold material for 3D printing comprises 50-90% of degradable high polymer material, 5-50% of bioactive ceramic and 0.5-5% of quantum dots in percentage by weight.

When the degradable high polymer material, the bioactive ceramic and the quantum dots are combined in the specific mass ratio relationship in the artificial bone scaffold material for 3D printing, the artificial bone scaffold material has better effects on the aspects of improving the mechanical property of the material and stabilizing a fluorescence signal.

The degradable high polymer material can be 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% by weight.

The bioactive ceramic may be present in an amount of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or the like, by weight.

The quantum dots can be 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% by weight.

Other specific point values within the above numerical ranges can be selected, and are not described in detail herein.

Preferably, the degradable high polymer material is selected from any one or a combination of at least two of polyglycolide, polylactide, polylactic acid-glycolic acid copolymer, polycaprolactone or polyhydroxyalkanoate.

The combination of at least two of them, such as the combination of polyglycolide and polylactide, the combination of polylactic acid-glycolic acid copolymer and polycaprolactone, the combination of polycaprolactone and polyhydroxyalkanoate, and the like, can be selected in any combination mode, and is not repeated herein.

Preferably, the degradable high molecular material is selected from the combination of polylactide and polycaprolactone.

Preferably, the mass ratio of the polylactide to the polycaprolactone is (3-5):1, for example, 3:1, 3.5:1, 4:1, 4.5:1 or 5:1, and other specific values within the numerical range can be selected, and are not described in detail herein.

The degradable high polymer material is more preferably a combination of polylactide and polycaprolactone, and further has more remarkable advantages in synergistic combination with bioactive ceramics when combined in a specific mass ratio.

Preferably, the bioactive ceramic is selected from any one of calcium phosphate ceramic, calcium silicate ceramic or bioactive glass or a combination of at least two of the same.

The combination of at least two of the calcium phosphate ceramic and the calcium silicate ceramic, the calcium silicate ceramic and the bioactive glass, the calcium phosphate ceramic and the bioactive glass, and the like can be selected in any combination manner, and are not repeated herein.

A combination of calcium phosphate ceramic and calcium silicate ceramic is preferred.

Preferably, the calcium phosphate ceramic comprises any one of hydroxyapatite, β -tricalcium phosphate or biphasic calcium phosphate, or a combination of at least two of these.

The combination of at least two of the above-mentioned components, such as the combination of hydroxyapatite and β -tricalcium phosphate, the combination of β -tricalcium phosphate and biphasic calcium phosphate, the combination of hydroxyapatite and biphasic calcium phosphate, etc., may be selected in any combination manner, and thus, the details thereof are not repeated herein.

Preferably, the calcium silicate ceramic comprises any one of calcium silicate, dicalcium silicate, tricalcium silicate, diopside, akermanite or whitlaite, or a combination of at least two thereof.

The combination of at least two of the above-mentioned materials, such as the combination of calcium silicate and dicalcium silicate, the combination of tricalcium silicate and diopside, the combination of akermanite and whitlaite, etc., can be selected in any combination manner, and thus, the details are not repeated herein.

Preferably, the bioactive glass is a silicate glass containing silicon oxide, sodium oxide, calcium oxide and phosphorus oxide.

Preferably, the bioactive ceramic is selected from the group consisting of hydroxyapatite and calcium silicate in combination.

Preferably, the mass ratio of the hydroxyapatite to the calcium silicate is 1:3-3:1, for example, 1:3, 1:2, 1:1, 2:1 or 3:1, and other specific values within the numerical range can be selected, and are not described herein again.

The bioactive ceramic is more preferably a combination of hydroxyapatite and calcium silicate, and further has more remarkable advantages in synergistic combination with a degradable high polymer material when combined in a specific mass ratio, and has more remarkable effect on performance stability of quantum dots.

Preferably, the particle size of the bioactive ceramic is 50nm-10 μm, for example, 50nm, 100nm, 500nm, 1 μm, 2 μm, 5 μm or 10 μm, and other specific values within the numerical range can be selected, and are not described in detail herein.

Preferably, the quantum dots are selected from any one of or a combination of at least two of CdTe, CdS, CdSe, ZnSe, ZnO, CdSe/ZnS, CdSe/CdS or CdS/ZnS.

The combination of at least two of the above-mentioned combinations, such as the combination of CdTe and CdS, the combination of CdSe and ZnSe, the combination of CdSe/ZnS and CdSe/CdS, etc., can be selected in any other combination manner, and will not be described in detail herein.

Preferably, the particle size of the quantum dot is 2-20nm, such as 2nm, 5nm, 10nm, 12nm, 15nm, 18nm or 20nm, and other specific values in the numerical range can be selected, which is not described herein again.

Preferably, the surface of the quantum dot is modified with a functional modifier, for example, the stability and the compatibility with organisms of the quantum dot can be increased.

In a second aspect, the present invention provides a method for preparing the artificial bone scaffold material for 3D printing according to the first aspect, the method comprising the following steps:

(4) and (4) extruding, drawing and drying the composite material granules obtained in the step (3) to obtain the artificial bone scaffold material for 3D printing.

Preferably, the organic solvent in step (1) comprises any one of dichloromethane, chloroform, tetrahydrofuran, acetone or ethyl acetate or a combination of at least two of the two.

The combination of at least two of the above-mentioned compounds, such as a combination of dichloromethane and chloroform, a combination of tetrahydrofuran and acetone, a combination of acetone and ethyl acetate, etc., any other combination mode can be selected, and thus, the details are not repeated herein.

Preferably, the mass percentage of the degradable polymer material in the organic solvent in step (1) is 2-8%, for example, 2%, 3%, 4%, 5%, 6%, 7%, or 8%, and other specific values within the range of values may be selected, and are not described herein again.

Preferably, the mass percentage content of the quantum dots in the degradable polymer/quantum dot composite material in step (1) is 0.5-5%, for example, 0.5%, 1%, 2%, 3%, 4%, or 5%, and other specific point values within the numerical range may be selected, and are not described herein again.

Preferably, the diameter of the artificial bone scaffold material for 3D printing in step (4) is 1.5-2mm, for example, 1.5mm, 1.6mm, 1.7mm, 1.8mm, 1.9mm, or 2mm, and other specific point values within the range of values may be selected, and are not described in detail herein.

In a third aspect, the invention provides an application of the artificial bone scaffold material for 3D printing in preparing an artificial bone.

Compared with the prior art, the invention has the following beneficial effects:

the artificial bone scaffold material for 3D printing, which is disclosed by the invention, is prepared by compounding degradable high polymer material, bioactive ceramic and quantum dots, effectively combining the rigidity, strength and bone conductivity of inorganic material with the strength, biodegradability and stable fluorescence effect of the quantum dots of the high polymer material, and realizing the synergistic cooperation of the three materials, so that the mechanical strength of the artificial bone scaffold material is remarkably improved compared with that of the pure high polymer material or bioactive ceramic, and the artificial bone scaffold material has the advantages of hardness, toughness and other biomechanics. Meanwhile, the degradation product of the bioactive ceramic is alkaline, so that the bioactive ceramic can be used for neutralizing high-molecular acidic degradation products, and the effects of delaying degradation speed and improving material bioactivity and biocompatibility are achieved. The addition of the quantum dots endows the bone scaffold material with a function of monitoring the development degradation rate under fluorescence, can be used for tracking the internalization absorption of the bone material, and compared with the existing fluorescent powder doping technology, the quantum dot fluorescent probe has the advantages of small scattering in the composite material, uniform dispersion and no agglomeration and precipitation phenomena; the quantum dots have longer service life than fluorescent dye, wide and continuous distribution of excitation spectrum, narrow and symmetrical emission spectrum, adjustable color and high photochemical stability, are more ideal fluorescent probe materials and are easy to obtain fluorescent signals without background interference; the bioactive ceramic can better isolate the internal quantum dots from the physiological environment, ensures the stable performance of the quantum dots, and gradually degrades the quantum dots to be slowly released so as to be safely metabolized out of the body.

Drawings

FIG. 1 is a fluorescent spectrum of the prepared scaffold materials of examples 1-4 and comparative example 1.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

Example 1

The embodiment provides an artificial bone scaffold material for 3D printing, and a preparation method thereof is as follows:

(1) weighing PLGA, dissolving the PLGA in dichloromethane to prepare a 5% solution, and performing ultrasonic stirring treatment at 25 ℃ until the PLGA is fully dissolved; then adding CdSe quantum dot toluene solution, and performing ultrasonic stirring treatment again to fully and uniformly mix the two solutions; and distilling the mixed solution at 40 ℃ and drying to constant weight to obtain the PLGA/CdSe composite material with the quantum dot content of 0.5%.

(2) And (3) blending, extruding and granulating the PLGA/CdSe composite material by using a double-screw extruder, and drying to obtain PLGA/CdSe composite material granules.

(3) And (3) blending, extruding, granulating and drying the PLGA/CdSe composite material granules and hydroxyapatite powder in a double-screw extruder according to the weight ratio of 5:1 to obtain the PLGA/CdSe/HAP composite material granules.