CN111249521B - Preparation method of composite porous scaffold material for bone repair - Google Patents
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Abstract
The invention discloses a preparation method of a composite porous scaffold material for bone repair, which belongs to the technical application field of biomedical materials, wherein gelatin and nano titanium dioxide are used as raw materials, an electrostatic spinning method is adopted to prepare the composite porous scaffold material, the preparation method can continuously prepare nano or submicron superfine fibers, the prepared bone porous scaffold has a unique microstructure and proper mechanical properties, and cell experiments show that the material has excellent biological properties and can be used in the field of bone repair.
Description
Technical Field
The invention relates to a preparation method of a composite porous scaffold material for bone repair, belonging to the field of biomedical materials.
Background
One area of scientific research in modern medicine has focused on human bones and other types of tissue, with the goal of developing artificial materials that can replace diseased areas of the human body. The bone tissue engineering scaffold material is a material which can be combined with osteoblast and can be implanted into organism, and is the most basic framework of tissue engineering bone. After the scaffold material is implanted into an organism, the scaffold material and the contact part of host tissues are chemically combined, so that the scaffold material can play a role for a long time without loosening and damaging at an interface.
Bone tissue engineering includes 3 key factors: growth factors, scaffold materials and seed cells. The selection of the scaffold material is the core problem of bone and cartilage tissue engineering, and the final purpose of the scaffold material is clinical application, so the ideal bone scaffold material has the following conditions: the biological compatibility is good, the inflammatory reaction is not easy to occur, and the cell adhesion is facilitated; ② has certain mechanical strength; good biological activity; the structure is favorable for inputting nutrient substances and discharging metabolic waste, thereby being favorable for the metabolism of bone cells; good biological degradability, which is good for cell proliferation, and the degradation rate of the bracket should match with the proliferation rate of the cell.
At present, bone tissue engineering scaffold materials are mainly classified into three types: biologically derived materials, inorganic materials and polymeric materials. The natural derivative materials mainly comprise collagen, chitin, alginate, fibrin and the like, and the materials can promote cell adhesion, proliferation and matrix secretion, have good biocompatibility, are not easy to produce on a large scale and lack strength. The inorganic materials are mainly bioceramics and bioactive glasses. The biological ceramics mainly comprise calcium sulfate ceramics, calcium carbonate ceramics, calcium phosphate ceramics and isomers thereof. Calcium phosphate ceramics represented by hydroxyapatite are one of widely used bone substitute materials, and all of them have good biocompatibility, biodegradability and osteoconductivity. But has the problems of large brittleness, insufficient flexibility, difficult degradation in vivo, influence on the growth of new bones, later reconstruction and the like. High molecular materials represented by polylactic acid, polyglycolic acid, copolymers thereof, and the like are widely used. The biological high molecular material has good biodegradability, biocompatibility, safety, nontoxicity and certain mechanical property, and can be processed into various structural shapes by the technologies of molding, extrusion, solvent casting and the like. Can be made into fiber bracket, porous foam, tubular structure, etc. according to the requirement, thereby leading the new bone tissue to have ideal shape. However, many scaffold materials for bone tissue engineering exist at present, each scaffold material has its advantages and disadvantages, the existing scaffold material can only meet a part of the requirements of an ideal scaffold material, and with the continuous and deep research, the composite scaffold material becomes one of the current research hotspots.
Collagen is one of the most abundant of various kinds of collagen contained in the human body, and is present in muscle, skin, arterial wall, and fibrocartilage, and can be extracted from animal tissues. The collagen has excellent biological properties, such as low antigenicity, blood coagulation, and the ability to regulate cell adhesion, proliferation, differentiation, etc. Therefore, collagen is commonly used for the preparation of tissue engineering scaffolds. The collagen scaffold is degraded into corresponding small molecular polypeptides and amino acids under the action of collagenase or metalloprotease in vivo, and enters the blood circulation process or is phagocytized by cells and further decomposed and absorbed, so that the collagen is very easy to be absorbed by human bodies when being used as an in vivo transplantation material.
The nanometer titanium dioxide is a photocatalyst, can well inhibit the growth of bacteria under illumination, and has good catalytic decomposition and cleaning effects on organic matters.
Disclosure of Invention
The invention provides a preparation method of a composite porous scaffold material for bone repair, which is characterized in that collagen is compounded with artificially synthesized nano titanium dioxide through electrostatic spinning to obtain a nano fiber scaffold material.
A preparation method of a composite porous scaffold material for bone repair specifically comprises the following steps:
(1) mixing butyl titanate, ethanol and acetic acid according to the mass volume ratio of g: mL: mL of 10-20:100:25 at room temperature, and magnetically stirring for 3-5h to form titanium alcohol liquid;
(2) mixing polyvinylpyrrolidone with the titanium alcohol solution obtained in the step (1) according to the mass-volume ratio of 8-9:10, performing ultrasonic dispersion for 20-50min, and performing magnetic stirring for 1-2h to obtain a dispersed titanium solution;
(3) adding the dispersed titanium solution obtained in the step (2) into an electrospinning device for electrostatic spinning to obtain a nanofiber membrane;
(4) placing the nanofiber membrane obtained in the step (3) in an air atmosphere resistance furnace, heating to 500 ℃, and preserving heat for 2-5 hours to obtain nano titanium dioxide;
(5) adding collagen into a hexafluoroisopropanol solution at room temperature according to the mass volume ratio g: mL of 7-12:100 of the collagen and the hexafluoroisopropanol, and magnetically stirring for 1-2h to obtain a collagen solution, wherein the collagen is type I collagen;
(6) adding the nano titanium dioxide obtained in the step (4) into the collagen solution obtained in the step (5), and performing ultrasonic dispersion for 5-10min to obtain a spinning stock solution;
(7) adopting a flat receiver, connecting the positive pole of a power supply with a needle head, connecting the negative pole with a steel plate, carrying out electrostatic spinning on the spinning solution obtained in the step (6) to obtain spinning fibers, and crosslinking the spinning fibers by using a crosslinking agent;
(8) and (4) freeze-drying the material crosslinked in the step (7) for 48 hours to obtain the composite porous scaffold material for bone repair.
The magnetic stirring speed in the step (1) is 100-400 r/min.
The ultrasonic frequency of the ultrasonic dispersion in the step (2) is 20-40kHz, and the temperature is 40-50 ℃.
The magnetic stirring speed in the step (2) is 100-400 r/min.
In the step (3), the voltage of electrostatic spinning is 16-20kV, the advancing speed is 0.1-0.2mm/min, the receiving distance is 15-25cm, and the number of the used needle is 17-20.
The magnetic stirring speed in the step (5) is 100-200 r/min.
In the step (6), the mass-volume ratio g: mL of the nano titanium dioxide to the collagen solution is 0.1-0.5: 100.
The ultrasonic frequency of the ultrasonic dispersion in the step (6) is 10-20 kHz.
In the step (7), the voltage of electrostatic spinning is 13-25kV, the advancing speed is 0.1-0.2mm/min, the receiving distance is 15-25cm, and the number of the used needle is 17-20.
In the step (8), the cross-linking agent is a mixture of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxy thiosuccinimide (EDC/NHS) in a mass ratio of 6:1, glutaraldehyde or citric acid, and the cross-linking time is 24-36 h.
The invention has the beneficial effects that:
(1) the collagen and the nano titanium dioxide used in the invention have no cytotoxicity and good biocompatibility.
(2) The invention can better control the fiber quality and the fiber diameter distribution by changing relevant parameters of electrostatic spinning, and the structure is suitable for cell adhesion growth and nutrient substance transportation.
(3) The thickness of the obtained bone repair support can be adjusted by adjusting the spinning time.
(4) The invention solves the problem of poor activity of titanium dioxide powder, and the nano titanium dioxide prepared by electrostatic spinning has higher catalytic activity.
Drawings
FIG. 1 is an SEM image of nano-titania obtained in example 1 of the present invention;
FIG. 2 is an XRD spectrum of nano titanium dioxide obtained in example 1 of the present invention;
FIG. 3 is an SEM photograph of the composite porous scaffold material for bone repair obtained in example 1 of the present invention;
FIG. 4 is an SEM photograph of the composite porous scaffold material for bone repair obtained in example 2 of the present invention;
FIG. 5 is an SEM photograph of the composite porous scaffold material for bone repair obtained in example 3 of the present invention.
Detailed Description
The invention will be described in more detail with reference to the following figures and examples, but the scope of the invention is not limited thereto.
Example 1
A preparation method of a composite porous scaffold material for bone repair specifically comprises the following steps:
(1) at room temperature, 1g of butyl titanate, 10mL of ethanol and 2.5mL of acetic acid are fully mixed, and are magnetically stirred for 3 hours at the speed of 100r/min to form titanium alcohol liquid;
(2) adding 8g of polyvinylpyrrolidone into 10mL of titanium alcohol solution, performing ultrasonic dispersion at the frequency of 20kHz and the temperature of 50 ℃ for 20min, and magnetically stirring at the speed of 400r/min for 1h to obtain dispersed titanium solution;
(3) adopting a No. 17 needle, setting the positive voltage to be 16KV, the negative voltage to be-3.5 KV, setting the injection speed of the spinning solution to be 0.1mm/min, setting the distance between the needle and a receiving device to be 15cm, connecting the positive electrode of a power supply with the needle, connecting the negative electrode with a steel plate, and carrying out electrostatic spinning on the dispersed titanium solution obtained in the step (2) to obtain a nanofiber membrane;
(4) placing the obtained nanofiber membrane in a resistance furnace, heating to 500 ℃ in air atmosphere, and preserving heat for 2 hours to obtain nano titanium dioxide;
(5) dissolving 7g of collagen in 100mL of hexafluoroisopropanol at room temperature, and magnetically stirring at the speed of 200r/min for 1h to obtain a collagen solution, wherein the collagen is type I collagen;
(6) adding nano titanium dioxide into a collagen solution, and performing ultrasonic dispersion at 10kHz for 10min to obtain a spinning stock solution, wherein the mass volume ratio g: mL of the nano titanium dioxide to the collagen solution is 0.1: 100;
(7) adopting a No. 17 needle head, setting the positive voltage to be 13KV, the negative voltage to be-3.5 KV, setting the injection speed of the spinning solution to be 0.1mm/min, setting the distance between the needle head and a receiving device to be 15cm, connecting the positive pole of a power supply with the needle head, connecting the negative pole with a steel plate, carrying out electrostatic spinning on the spinning solution to obtain spinning fibers, and crosslinking the spinning fibers for 24 hours by using glutaraldehyde;
(8) and (3) freeze-drying the cross-linked material for 48 hours to obtain the composite porous scaffold material for bone repair.
FIG. 1 is an SEM image of the nano-titania obtained in step (4) of this example; the obtained nano titanium dioxide has better size and structure, and has better catalytic activity compared with powder.
FIG. 2 is an XRD spectrum of the nano titanium dioxide obtained in the present example; comparing the characteristic peaks of the diffraction of the crystal faces of the standard titanium dioxide in the figure, the anatase type titanium dioxide and the rutile type titanium dioxide are successfully prepared, and the crystallinity is good.
FIG. 3 is an SEM image of the final porous material for bone repair prepared in this example, which shows that the obtained porous fiber material has fiber diameter distribution of 800-900nm, uniform fiber diameter, smooth fiber surface, and porous structure formed between fibers is easy for cell growth and adhesion.
The composite porous scaffold material for bone repair obtained in the embodiment has a tensile strength of 5.2MPa and cytotoxicity of 0 grade, that is, has no cytotoxicity.
Example 2
A preparation method of a composite porous scaffold material for bone repair specifically comprises the following steps:
(1) at room temperature, 1.5g of butyl titanate, 10mL of ethanol and 2.5mL of acetic acid are fully mixed, and are magnetically stirred for 4 hours at the speed of 200 r/min; forming titanium alcohol liquid;
(2) adding 8.5g of polyvinylpyrrolidone into 10mL of titanium alcohol solution, performing ultrasonic dispersion at the frequency of 30kHz and the temperature of 45 ℃ for 35min, and magnetically stirring at the speed of 200r/min for 1.5h to obtain dispersed titanium solution;
(3) adopting a 19-gauge needle, setting the positive voltage to be 18KV, the negative voltage to be-3.5 KV, the injection speed of the spinning solution to be 0.15mm/min, the distance between the needle and a receiving device to be 20cm, connecting the positive pole of a power supply with the needle, connecting the negative pole with a steel plate, and carrying out electrostatic spinning on the dispersed titanium solution to obtain a nanofiber membrane;
(4) placing the obtained nanofiber membrane in a resistance furnace, heating to 500 ℃ in air atmosphere, and preserving heat for 3 hours to obtain nano titanium dioxide;
(5) dissolving 10g of collagen in 100mL of hexafluoroisopropanol at room temperature, and magnetically stirring at the speed of 150r/min for 1.5h to obtain a collagen solution, wherein the collagen is type I collagen;
(6) adding nano titanium dioxide into a collagen solution, and ultrasonically dispersing for 7min at 15kHz to obtain a spinning stock solution, wherein the mass volume ratio g: mL of the nano titanium dioxide to the collagen solution is 0.3: 100;
(7) adopting a 19-gauge needle, setting the positive voltage to be 18KV, the negative voltage to be-3.5 KV, the injection speed of the spinning solution to be 0.15mm/min, the distance between the needle and a receiving device to be 20cm, connecting the positive pole of a power supply with the needle, connecting the negative pole with a steel plate, carrying out electrostatic spinning on the spinning solution to obtain spinning fibers, and crosslinking the spinning fibers for 30 hours by adopting citric acid;
(8) and (3) freeze-drying the cross-linked material for 48 hours to obtain the composite porous scaffold material for bone repair.
FIG. 4 is an SEM image of the final porous material for bone repair prepared in this example, which shows that the obtained porous fiber material has fiber diameter distribution of 500-700nm, uniform fiber diameter, smooth fiber surface, and porous structure formed between fibers is easy for cell growth and adhesion.
The composite porous scaffold material for bone repair obtained in the embodiment has tensile strength of 4.9MPa and cytotoxicity of 0 grade, namely, has no cytotoxicity.
Example 3
A preparation method of a composite porous scaffold material for bone repair specifically comprises the following steps:
(1) at room temperature, 2g of butyl titanate, 10mL of ethanol and 2.5mL of acetic acid are fully mixed, and magnetic stirring is carried out at the speed of 100r/min for 5 hours; forming titanium alcohol liquid;
(2) adding 9g of polyvinylpyrrolidone into 10mL of titanium alcohol solution, performing ultrasonic dispersion at 40kHz and 40 ℃ for 50min, and magnetically stirring at 100r/min for 2h to obtain dispersed titanium solution;
(3) adopting a No. 20 needle head, setting the positive voltage to be 20KV, the negative voltage to be-3.5 KV, setting the injection speed of the spinning solution to be 0.2mm/min, setting the distance between the needle head and a receiving device to be 25cm, connecting the positive pole of a power supply with the needle head, connecting the negative pole with a steel plate, and carrying out electrostatic spinning on the dispersed titanium solution to obtain a nanofiber membrane;
(4) placing the obtained nanofiber membrane in a resistance furnace, heating to 500 ℃ in air atmosphere, and preserving heat for 5 hours to obtain nano titanium dioxide;
(5) dissolving 12g of collagen in 100mL of hexafluoroisopropanol at room temperature, and magnetically stirring at the speed of 100r/min for 2 hours to obtain a collagen solution, wherein the collagen is type I collagen;
(6) adding nano titanium dioxide into a collagen solution, and ultrasonically dispersing for 5min at 20kHz to obtain a spinning stock solution, wherein the mass volume ratio g: mL of the nano titanium dioxide to the collagen solution is 0.5: 100;
(7) adopting a No. 20 needle, setting the positive voltage to be 25KV, the negative voltage to be-3.5 KV, setting the injection speed of the spinning solution to be 0.2mm/min, setting the distance between the needle and a receiving device to be 25cm, connecting the positive electrode of a power supply to the needle, connecting the negative electrode of the power supply to a steel plate, carrying out electrostatic spinning on the spinning solution to obtain spinning fibers, and crosslinking the spinning fibers for 36h by adopting a mixture of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxy thiosuccinimide (EDC/NHS) in a mass ratio of 6: 1;
(8) and (3) freeze-drying the cross-linked material for 48 hours to obtain the composite porous scaffold material for bone repair.
FIG. 5 is an SEM image of the final porous material for bone repair prepared in this example, which shows that the obtained porous fiber material has fiber diameter distribution of 200-400nm, uniform fiber diameter, smooth fiber surface, and porous structure formed between fibers for easy cell growth and adhesion.
The composite porous scaffold material for bone repair obtained in the embodiment has tensile strength of 4.7MPa and cytotoxicity of 0 grade, namely, has no cytotoxicity.
The composite porous scaffold material for bone repair prepared by the invention has abundant pore structures, is easy for cell growth and proliferation, and cell experiments show that the material has good bioactivity and biocompatibility and good mechanical properties, can be used as a bone tissue engineering scaffold and is applied to the field of bone repair.
Claims (8)
1. A preparation method of a composite porous scaffold material for bone repair is characterized by comprising the following steps:
(1) mixing butyl titanate, ethanol and acetic acid according to the mass volume ratio of g: mL: mL of 10-20:100:25 at room temperature, and magnetically stirring for 3-5h to form titanium alcohol liquid;
(2) mixing polyvinylpyrrolidone with the titanium alcohol solution obtained in the step (1) according to the mass-volume ratio of 8-9:10, performing ultrasonic dispersion for 20-50min, and performing magnetic stirring for 1-2h to obtain a dispersed titanium solution;
(3) performing electrostatic spinning on the dispersed titanium solution obtained in the step (2) to obtain a nanofiber membrane;
(4) keeping the nanofiber membrane obtained in the step (3) at 500 ℃ for 2-5h in an air atmosphere to obtain nano titanium dioxide;
(5) adding collagen into a hexafluoroisopropanol solution at room temperature according to the mass volume ratio g: mL of 7-12:100 of the collagen and the hexafluoroisopropanol, and magnetically stirring for 1-2h to obtain a collagen solution, wherein the collagen is type I collagen;
(6) adding the nano titanium dioxide obtained in the step (4) into the collagen solution obtained in the step (5), and performing ultrasonic dispersion for 5-10min to obtain a spinning stock solution; the mass volume ratio g: mL of the nano titanium dioxide to the collagen solution is 0.1-0.5: 100;
(7) adopting a flat receiver, connecting the positive pole of a power supply with a needle head, connecting the negative pole with a steel plate, carrying out electrostatic spinning on the spinning solution obtained in the step (6) to obtain spinning fibers, and crosslinking the spinning fibers by using a crosslinking agent; the cross-linking agent is a mixture of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxy sulphosuccinimide in a mass ratio of 6:1 or citric acid, and the cross-linking time is 24-36 h;
(8) and (4) freeze-drying the material crosslinked in the step (7) for 48 hours to obtain the composite porous scaffold material for bone repair.
2. The method for preparing a composite porous scaffold material for bone repair as claimed in claim 1, wherein the magnetic stirring speed in step (1) is 100-400 r/min.
3. The method for preparing a composite porous scaffold material for bone repair according to claim 1, wherein the ultrasonic frequency of the ultrasonic dispersion in the step (2) is 20 to 40kHz and the temperature is 40 to 50 ℃.
4. The method for preparing a composite porous scaffold material for bone repair as claimed in claim 1, wherein the magnetic stirring speed in step (2) is 100-400 r/min.
5. The method for preparing a composite porous scaffold material for bone repair according to claim 1, wherein the voltage of electrospinning in the step (3) is 16-20kV, the advancing speed is 0.1-0.2mm/min, the receiving distance is 15-25cm, and the needle used is 17-20 gauge.
6. The method for preparing a composite porous scaffold material for bone repair as claimed in claim 1, wherein the magnetic stirring speed in step (5) is 100-200 r/min.
7. The method for preparing a composite porous scaffold material for bone repair according to claim 1, wherein the ultrasonic frequency of the ultrasonic dispersion in the step (6) is 10 to 20 kHz.
8. The method for preparing a composite porous scaffold material for bone repair according to claim 1, wherein the voltage of electrospinning in the step (7) is 13-25kV, the advancing speed is 0.1-0.2mm/min, the receiving distance is 15-25cm, and the needle used is 17-20 gauge.
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