CN109675101B - Chitin nano whisker/hydroxyapatite composite material, preparation method thereof and application thereof in 3D printing of artificial bone - Google Patents

Chitin nano whisker/hydroxyapatite composite material, preparation method thereof and application thereof in 3D printing of artificial bone Download PDF

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CN109675101B
CN109675101B CN201910010217.3A CN201910010217A CN109675101B CN 109675101 B CN109675101 B CN 109675101B CN 201910010217 A CN201910010217 A CN 201910010217A CN 109675101 B CN109675101 B CN 109675101B
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chitin
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composite material
hydroxyapatite
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CN109675101A (en
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曾庆丰
魏静
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Xi'an Particle Cloud Biotechnology Co ltd
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Xi'an Particle Cloud Biotechnology Co ltd
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Abstract

The invention discloses a chitin nano whisker/hydroxyapatite composite material, a preparation method thereof and application thereof in 3D printing of artificial bones. The preparation method adds the chitin nano crystal whisker into CaCl by an in-situ synthesis method2In solution, on the basis of which (NH) is added4)2HPO4The solution is used for forming hydroxyapatite and compounding the chitin nanowhiskers into the hydroxyapatite material; when the prepared composite material has the characteristic of high hydroxyapatite strength, the aim of enhancing the toughness of the biological material by using the whiskers is utilized, and meanwhile, the chitin enables the material to have good bone conduction, bone induction and biocompatibility, and also has the effects of diminishing inflammation, easing pain, resisting coagulation and promoting wound healing; the chitin nano whisker/hydroxyapatite composite material is applied to the preparation of artificial bones, and compared with the artificial bones prepared from pure hydroxyapatite materials, the compression strength of the artificial bones is improved by 40.3 percent, and the elastic modulus is reduced by 19.8 percent.

Description

Chitin nano whisker/hydroxyapatite composite material, preparation method thereof and application thereof in 3D printing of artificial bone
[ technical field ] A method for producing a semiconductor device
The invention belongs to the technical field of medical treatment, and particularly relates to a chitin nano whisker/hydroxyapatite composite material, a preparation method thereof and application thereof in 3D printing of artificial bones.
[ background of the invention ]
Bone defects caused by fracture, bone tumor, trauma and infection, etc. require bone graft repair treatment. Bone transplantation includes autologous bone transplantation, allogeneic bone transplantation, xenogeneic bone transplantation, artificial bone transplantation, and the like. The artificial bone transplantation is a necessary trend in the field of bone repair due to the breakthrough of source limitation, avoidance of immune and virus risks and the like.
In recent years, the preparation of artificial bone scaffolds has been rapidly developed in bone tissue engineering, various new materials are used to prepare bone scaffolds, and complementary mechanisms of various materials are applied to prepare composite scaffolds, so as to improve the mechanical and biological properties of the prepared scaffolds. Meanwhile, the preparation technology of the porous scaffold is continuously updated, and the porous scaffold capable of meeting the requirements of a human body is prepared by different methods. The method for rapidly manufacturing the personalized artificial bone by using the bone tissue engineering material by adopting the 3D printing technology has great academic significance, solves the manufacturing problem of the bone-induced artificial bone, and gradually forms a new industry with great market potential. If the 3D printing artificial bone technology is popularized in the treatment of orthopedic diseases, higher-quality bone repair treatment can be brought to human beings.
The bioceramic material has gradually become a hotspot and a key point in the field of bone graft repair due to good biocompatibility, degradability, osteoinduction and osteoconductivity. The hydroxyapatite has a molecular formula of Ca because of similarity with human skeleton components10(PO4)6(OH)2Has excellent biocompatibility and bone affinity, is superior to medical titanium, silicon rubber, bone grafting carbon material and other medical implanting materials, and is widely applied to clinic. In addition, hydroxyapatite has excellent osteoconductivity and osseointegration capability, no toxic or side effect and no carcinogenic effect, so that hydroxyapatite is widely applied to physiological scaffolds of bone filling materials and bone repair materials in diseases and accidents. However, the single hydroxyapatite material inevitably has some performance defects, such as low fracture toughness and poor fatigue resistance, is only used for repairing bone defects of non-bearing parts, and is difficult to degrade and absorb by organisms. Therefore, the single material is difficult to meet the requirements of bone repair, and the development of bone repair composite materials is not slow.
Chitin, also known as chitin, is a glycosaminoglycan polymer formed by the condensation of N-acetylglucosamine by beta-1, 4 glycosidic bonds. The macromolecular structure of chitin is the same as the composition of glucosamine in human body, and has a structure similar to human ossein tissue, and the double structure makes it have excellent biomedical characteristics: it has no toxicity and irritation to human body, strong affinity with body cell, excellent biocompatibility with human tissue, wound healing promoting, antibacterial, antiphlogistic, hemostatic, analgesic, antiviral, anticoagulant and other functions.
The chitin nano crystal whisker is chitin fiber existing in a single crystal form and is formed by orderly stacking chitin molecules, so that the chitin nano crystal whisker has all good properties of chitin. Meanwhile, the chitin nanowhiskers have extremely small diameters (nanometer magnitude order), do not contain the defects of crystal boundaries, dislocation, cavities and the like of common materials, and have highly ordered atomic arrangement, so the chitin nanowhiskers have the characteristics of high strength and high modulus, and are natural reinforced materials with excellent performance and environmental friendliness.
The hydroxyapatite and the chitin nano crystal whisker have no harm to human bodies, and the chitin has the characteristics of high strength and high modulus, so that how to combine the hydroxyapatite and the chitin nano crystal whisker to prepare the artificial bone suitable for human bodies has not been reported.
[ summary of the invention ]
The invention aims to overcome the defects of the prior art and provides a chitin nano whisker/hydroxyapatite composite material, a preparation method thereof and application thereof in 3D printing of artificial bones; the composite material is prepared by compounding nano chitin whisker and hydroxyapatite and can be used as a raw material for 3D printing of artificial bones.
In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:
a preparation method of a chitin nano whisker/hydroxyapatite composite material comprises the following steps: adding chitin nano whisker into CaCl2Adding (NH) while stirring to the solution4)2HPO4After the addition of the solution is finished, continuously stirring the solution until the solution is uniform to obtain a mixed solution; adding ammonia water into the mixed solution, adjusting the pH value of the mixed solution to 9-11, simultaneously heating the whole mixed solution to 100-120 ℃ to obtain a reaction system A, and reacting the reaction system A at the temperature to obtain the catalystTo process product B; and washing the process product B to obtain concentrated slurry, and drying the concentrated slurry to obtain the chitin nano whisker/hydroxyapatite composite material.
The invention is further improved in that:
preferably, the chitin nanowhiskers and CaCl2The material-liquid ratio of the solution is as follows: (15-23) g is 1L; added (NH)4)2HPO4Solution and CaCl2Equal volume of solution.
Preferably, CaCl2The concentration of the solution was 0.5mol/L, (NH)4)2HPO4The concentration of the solution was 0.3 mol/L.
Preferably, the preparation process of the chitin nanowhisker comprises the following steps: adding chitin into hydrochloric acid solution, and stirring to react to form a colloidal product; diluting and centrifuging the colloidal product to obtain colloidal chitin nanowhiskers; and dialyzing the colloidal chitin nanowhiskers to obtain chitin nanowhisker suspension, and freeze-drying to obtain the chitin nanowhiskers.
Preferably, the concentration of the hydrochloric acid solution is 3mol/L, and the mixing ratio of the chitin to the hydrochloric acid solution is (2-5) g:100 mL; adding chitin into a hydrochloric acid solution, stirring and heating until boiling for reaction for 2-4 hours to form a colloidal product; adding water into the colloidal product, wherein the added water submerges the colloidal product, and stirring to form a mixed solution; centrifuging the mixed solution, and removing supernatant; adding water into the centrifugal product and repeating the centrifugal treatment to obtain colloidal chitin nano crystal whisker.
Preferably, dialyzing the colloidal chitin nanowhiskers comprises the steps of: putting the colloidal chitin nano whisker into a dialysis bag for first dialysis, wherein the dosage of a dialysate is 20-50 times of the volume of the chitin nano whisker, the dialysis time is 8-12 h, and the dialysate is deionized water; and after the first dialysis is finished, performing second dialysis by taking deionized water as dialysate, finishing the dialysis when the pH value of the dialysate is 7, and preparing the chitin nano whisker suspension in a dialysis bag.
Preferably, CaCl2The solution can pass Ca (NO)3)2The solution is replaced by the solution, and the solution is replaced by the solution,(NH4)2HPO4the solution can pass through Na2HPO4Replacing the solution; the reaction system A reacts for 24 hours to obtain a process product B; and drying the concentrated slurry at the temperature of 80-90 ℃.
The chitin nano whisker/hydroxyapatite composite material prepared by the preparation method is formed by compounding the chitin nano whisker and hydroxyapatite, and the chitin nano whisker is attached to the hydroxyapatite.
Preferably, the average diameter of the cross section of the chitin nano whisker is 25nm, and the length of the whisker is 150 nm-300 nm.
The chitin nano whisker/hydroxyapatite composite material can be mixed with an adhesive to form mixed slurry for 3D printing of the artificial bone.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses a preparation method of chitin nano whisker/hydroxyapatite composite material, which adds chitin nano whisker into CaCl by in-situ synthesis method2In solution, on the basis of which (NH) is added4)2HPO4The solution is used for forming hydroxyapatite and compounding the chitin nanowhiskers into the hydroxyapatite material; the method has the advantages of convenient operation and low synthesis cost, and the prepared composite material has fine and uniform size, no pollution on the surface of the chitin nano whisker, good wettability with hydroxyapatite and high interface bonding strength. The rod-shaped or short fiber-shaped whisker has the characteristics of high specific strength, high specific modulus, good creep resistance and high-temperature performance, is compounded with a material, absorbs energy by the bridging, crack deflection and pulling-out effects of the whisker, eliminates stress concentrated at the tip of a crack, and enables the stress to act on the whisker through load transfer, thereby reducing the stress borne by the surrounding matrix material, achieving the purpose of enhancing the toughness of the biomaterial and effectively improving the mechanical property of the artificial bone material; the composite material prepared by the method can ensure the nanometer-level carapaceThe cellulose whisker is attached to the hydroxyapatite, and the characteristics of the whisker and the chitin material are fully exerted.
The invention discloses a chitin nano whisker/hydroxyapatite composite material, which is characterized in that the chitin nano whisker is added into hydroxyapatite, and the performance of the hydroxyapatite is optimized by using the chitin nano whisker, so that when the material has the characteristic of high strength of the hydroxyapatite, the aim of enhancing the toughness of a biological material by using the whisker is fulfilled; meanwhile, the chitin enables the material to have good bone conduction, bone induction and biocompatibility, and also has the effects of diminishing inflammation, easing pain, resisting coagulation and promoting wound healing; the material can be directly used as a bone repair material.
The invention also discloses an application of the chitin nano whisker/hydroxyapatite composite material in 3D printing of the artificial bone; the chitin nano whisker/hydroxyapatite composite material is applied to the preparation of artificial bones, and compared with the artificial bones prepared from pure hydroxyapatite materials, the compression strength of the artificial bones is improved by 40.3 percent, and the elastic modulus is reduced by 19.8 percent, so that the composite material has better artificial bone strength and better toughness; on the other hand, the 3D printing technology is adopted to prepare the artificial bone with any aperture, porosity and appearance, thereby truly realizing the personalized and accurate treatment of the patient.
[ description of the drawings ]
FIG. 1 is a flow chart of the present invention for preparing chitin nanowhisker/hydroxyapatite composite material;
FIG. 2 is a TEM image of the chitin nanowhiskers prepared in the present invention;
FIG. 3 is an infrared spectrum of the chitin nanowhisker prepared in the present invention;
FIG. 4 is a flowchart of printing an artificial bone according to embodiment 1 of the present invention;
fig. 5 is a flowchart of printing an artificial bone according to embodiment 2 of the present invention.
[ detailed description ] embodiments
The invention is described in further detail below with reference to the figures and the specific steps. Referring to fig. 1, the preparation process of the chitin nanowhisker/hydroxyapatite composite material of the present invention specifically comprises the following steps:
step 1, preparing colloidal chitin nano whisker
Soaking 2-5 g of chitin in 100ml of hydrochloric acid, wherein the concentration of the hydrochloric acid is 3mol/L, placing the chitin in a triangular flask, and heating the chitin to boiling reaction for 2-4 hours under the stirring of mechanical force to form a colloidal product; adding water into the colloidal product to ensure that the added water can completely submerge the colloidal product so as to dilute the colloidal product, and uniformly stirring the mixture to form a mixed solution; centrifuging the mixed solution at the speed of 5000-9000 r/min for 6-10 min, then pouring out supernatant, and repeating the centrifuging operation once; and centrifuging to obtain colloidal chitin nanowhiskers.
Step 2, removing acidic substances in the colloidal chitin nanowhiskers
Putting the colloidal chitin nanowhiskers obtained in the step 1 into a dialysis bag, and carrying out primary dialysis for 8-12 h, wherein the dosage of dialysate is 20-50 times of that of the chitin nanowhiskers, and the dialysate is deionized water; using deionized water as dialysate to perform secondary dialysis on the chitin nanowhiskers, wherein the dosage of the dialysate is 20-50 times of that of the chitin nanowhiskers, and the pH value of the dialysate is intermittently detected during the dialysis process until the pH value of the dialysate is 7, so as to obtain a colloidal chitin nanowhisker suspension, and the deionized water is selected for the secondary dialysate to ensure that impurities such as ions in the chitin nanowhiskers are removed; freezing the chitin nano whisker suspension to be completely frozen, drying after freezing to obtain blocky chitin nano whiskers, and grinding to obtain powdery chitin nano whiskers, wherein the microstructure of the powdery chitin nano whiskers is chitin nano whiskers with the average diameter of 25nm and the length of 150 nm-300 nm no matter the powdery chitin nano whiskers are blocky chitin nano whiskers.
And 3, adding the chitin nanowhiskers into hydroxyapatite by an in-situ synthesis method to prepare the chitin nanowhiskers/hydroxyapatite composite material.
Adding the prepared powdery chitin nano whisker into 0.5mol/L CaCl in an amount of 15g/L to 23g/L in a reaction kettle2Or Ca (NO)3)2In solution; opening the reaction kettle to stirA stirring device with stirring speed of 35-60 r/min, and dropwise adding 0.3mol/L (NH) into the reaction kettle at a slower speed4)2HPO4Or Na2HPO4Added of (NH)4)2HPO4Or Na2HPO4Solution with CaCl2Or Ca (NO)3)2The volume of the solution is equal; and after the addition is finished, continuously stirring until the solution is uniformly mixed to obtain a mixed solution. Adding ammonia water into the mixed solution, adjusting the pH value of the solution to 9-11, simultaneously heating the whole reaction system to ensure that the temperature of the reaction system is 100-120 ℃ to obtain a reaction system A, and continuously stirring the solution in the whole process; the reaction system A reacts in a reaction kettle for 24 hours at the reaction temperature of 100-120 ℃, the whole process is continuously stirred, and a process product B is obtained after the reaction. The process product B was then washed with a ceramic membrane filter to obtain a concentrated slurry. And finally, drying the concentrated slurry at the temperature of 80-90 ℃ by a spray drying method to obtain the chitin nano whisker/hydroxyapatite composite material.
Fig. 2 is a TEM image of the chitin nanowhiskers prepared in the present invention; FIG. 3 is an infrared spectrum of the chitin nanowhisker prepared in the present invention; the chitin nanowhiskers prepared by the present invention can be seen by combining fig. 2 and fig. 3.
The composite material of the chitin nanowhiskers and the hydroxyapatite prepared by the method is an artificial bone repair material, has good bone conduction, bone induction and biocompatibility, has the effects of diminishing inflammation, easing pain, resisting coagulation and promoting wound healing, can be directly used as a bone repair material, and can also be prepared into a bone repair bracket of a porous structure by a 3D printing processing process.
The prepared composite repair material can be used for preparing artificial bones according to different individual differences through 3D printing, and the specific application process comprises the following steps:
(1) preparing an artificial bone material: preparing the chitin nano whisker/hydroxyapatite composite material according to the method;
(2) adhesive preparation: preparing a certain amount of polyvinyl alcohol and purified water into a polyvinyl alcohol aqueous solution with the mass fraction of 8% -12%, placing the polyvinyl alcohol aqueous solution in a solvent bottle with a cover, heating the polyvinyl alcohol aqueous solution in a water bath at 90-95 ℃ for about 2 hours, and intermittently shaking the polyvinyl alcohol aqueous solution in the heating process to accelerate the dissolution of the polyvinyl alcohol to obtain a uniform solution;
(3) mixing: mixing the artificial bone composite material prepared in the step (1) and an adhesive in a mass ratio of 1: 13-1: 15, and placing the mixture in a homogenizer to mix for 5-8 min at a rotating speed of 1600-2000 r/min to form uniformly mixed slurry.
(4) Three-dimensional reconstruction: the CT/MRI/X ray of the bone defect part of a patient is obtained, and a 3D printing artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure or special requirements is designed by utilizing three-dimensional reconstruction software such as Mimics research, E3D, 3matic, UG, 3D-med, slicer and the like.
(5) Printing: and printing the artificial bone by using a 3D biological ceramic printer. Firstly, filling the uniformly mixed printing slurry in the step (3) into a storage bin for high-speed centrifugal defoaming, then loading the designed artificial bone three-dimensional model STL file in the step (4) into PClab software, and setting the printing process parameters as follows: the printing speed is 10mm/s, the printing layer thickness is 150 micrometers, the average pore diameter is 450 micrometers, the slurry is uniformly extruded at a constant speed through a spiral propeller, the printing head moves along X, Y, Z directions, the printing is sequentially carried out layer by layer, and finally the printing of the customized 3D printing artificial bone is completed.
(6) And (3) freeze drying: placing the formed customized 3D printed artificial bone in the step (5) in a freeze drying box for freeze drying for 24 hours;
(7) and (3) sterilization: and (3) performing irradiation sterilization on the freeze-dried customized 3D printed artificial bone by using cobalt 60.
Example 1
Step 1, preparing colloidal chitin nano whisker
Soaking 2g of chitin in 100ml of hydrochloric acid, wherein the concentration of the hydrochloric acid is 3mol/L, placing the chitin in a triangular flask, and heating the chitin to boiling reaction for 4 hours under the stirring of mechanical force to form a colloidal product; adding water into the colloidal product to dilute the colloidal product, and uniformly stirring the mixture to form a mixed solution; centrifuging the mixed solution at a speed of 5000r/min for 10min, pouring out supernatant, and repeating the centrifuging operation; and centrifuging to obtain colloidal chitin nanowhiskers.
Step 2, removing acidic substances in the colloidal chitin nanowhiskers
Putting the chitin nano whiskers obtained in the step 1 into a dialysis bag, and performing first dialysis for 8 hours, wherein the dosage of a dialysate is 50 times that of the chitin nano whiskers, and the dialysate is tap water; then using deionized water as dialysate to carry out second dialysis until the PH value of the dialysate is 7 and the dosage of the dialysate is 20 times of that of the chitin nano whisker to obtain colloidal chitin nano whisker suspension; and (3) freezing the chitin nano whisker suspension until the chitin nano whisker is completely frozen, and drying after freezing to finally obtain the chitin nano whisker with the average diameter of 25nm and the length of 150 nm-300 nm.
And 3, adding the chitin nanowhiskers into hydroxyapatite by an in-situ synthesis method to prepare the chitin nanowhiskers/hydroxyapatite composite material.
Adding the prepared chitin nano crystal whisker into 0.5mol/L CaCl in an amount of 18g/L in a reaction kettle2In solution; opening a stirring device of the reaction kettle, setting the stirring speed to be 35r/min, and dropwise adding 0.3mol/L Na into the reaction kettle at a slower speed2HPO4Added Na2HPO4Solution with CaCl2The volume of the solution is equal; and after the addition is finished, continuously stirring until the solution is uniformly mixed to obtain a mixed solution. Then adding ammonia water into the mixed solution, adjusting the pH value of the solution to 11, heating the whole reaction system while adjusting the pH value of the solution to ensure that the reaction temperature of the reaction system is 100 ℃ to obtain a reaction system A, and continuously stirring the solution in the whole process; the reaction system A reacts in a reaction kettle for 24 hours at the reaction temperature of 100 ℃, the whole process is continuously stirred, and a process product B is obtained after the reaction. The process product B was then washed with a ceramic membrane filter to obtain a concentrated slurry. And finally, drying the concentrated slurry at 90 ℃ by a spray drying method to obtain the chitin nano whisker/hydroxyapatite composite material.
Step 4, 3D printing of the artificial bone material
(1) Preparing an artificial bone material: preparing 18g of chitin nano whisker/hydroxyapatite composite material;
(2) adhesive preparation: preparing polyvinyl alcohol aqueous solution with the mass fraction of 8% by 19g of polyvinyl alcohol and 218g of purified water, placing the polyvinyl alcohol aqueous solution in a solvent bottle with a cover, heating the solution in a water bath at 95 ℃ for about 2 hours, and intermittently shaking the solution in the heating process to accelerate the dissolution of the polyvinyl alcohol to obtain uniform solution;
(3) mixing: mixing the artificial bone composite material and the adhesive in a mass ratio of 1:13, and placing the mixture in a homogenizer for mixing for 8min at a rotating speed of 1800r/min to form uniformly mixed slurry.
(4) Three-dimensional reconstruction: the CT/MRI/X ray of the bone defect part of a patient is obtained, and a 3D printing artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure or special requirements is designed by utilizing three-dimensional reconstruction software such as Mimics research, E3D, 3matic, UG, 3D-med, slicer and the like.
(5) Printing: and printing the artificial bone by using a 3D biological ceramic printer. Firstly, filling the uniformly mixed printing slurry in the step (3) into a storage bin for high-speed centrifugal defoaming, then loading the designed artificial bone three-dimensional model STL file in the step (4) into PClab software, and setting the printing process parameters as follows: the printing speed is 10mm/s, the printing layer thickness is 150 micrometers, the average pore diameter is 450 micrometers, the slurry is uniformly extruded at a constant speed through a spiral propeller, the printing head moves along X, Y, Z directions, the printing is sequentially carried out layer by layer, and finally the printing of the customized 3D printing artificial bone is completed.
(6) And (3) freeze drying: placing the formed customized 3D printed artificial bone in the step (5) in a freeze drying box for freeze drying for 24 hours;
(7) and (3) sterilization: and (3) performing irradiation sterilization on the freeze-dried customized 3D printed artificial bone by using cobalt 60.
Example 2
Step 1, preparing colloidal chitin nano whisker
Soaking 5g of chitin in 100ml of hydrochloric acid, wherein the concentration of the hydrochloric acid is 3mol/L, placing the chitin in a triangular flask, and heating the chitin to boiling reaction for 3 hours under the stirring of mechanical force to form a colloidal product; adding water into the colloidal product to dilute the colloidal product, and uniformly stirring the mixture to form a mixed solution; centrifuging the mixed solution at 9000r/min for 6min, pouring out supernatant, and repeating the centrifuging operation; and centrifuging to obtain colloidal chitin nanowhiskers.
Step 2, removing acidic substances in the colloidal chitin nanowhiskers
Putting the chitin nano whiskers obtained in the step 1 into a dialysis bag, and performing primary dialysis for 12 hours, wherein the dosage of a dialysate is 20 times that of the chitin nano whiskers, and the dialysate is deionized water; then using deionized water as dialysate to carry out second dialysis until the PH value of the dialysate is 7 and the dosage of the dialysate is 50 times of that of the chitin nano whisker to obtain colloidal chitin nano whisker suspension; and (3) freezing the chitin nano whisker suspension until the chitin nano whisker is completely frozen, and drying after freezing to finally obtain the chitin nano whisker with the average diameter of 25nm and the length of 150 nm-300 nm.
And 3, adding the chitin nanowhiskers into hydroxyapatite by an in-situ synthesis method to prepare the chitin nanowhiskers/hydroxyapatite composite material.
Adding the prepared chitin nano whisker into 0.5mol/L Ca (NO) in an amount of 15g/L in a reaction kettle3)2In solution; opening a stirring device of the reaction kettle, setting the stirring speed to be 60r/min, and dropwise adding 0.3mol/L (NH) into the reaction kettle at a slower speed4)2HPO4Added of (NH)4)2HPO4Solution with Ca (NO)3)2The volume of the solution is equal; and after the addition is finished, continuously stirring until the solution is uniformly mixed to obtain a mixed solution. Then adding ammonia water into the mixed solution, adjusting the pH value of the solution to 9, heating the whole reaction system while adjusting the pH value of the solution to ensure that the reaction temperature of the reaction system is 120 ℃ to obtain a reaction system A, and continuously stirring the solution in the whole process; the reaction system A reacts in a reaction kettle for 24 hours at the reaction temperature of 120 ℃, the whole process is continuously stirred, and a process product B is obtained after the reaction. Then the process is producedAnd washing the substance B by using a ceramic membrane filter to obtain concentrated slurry. And finally, drying the concentrated slurry at 80 ℃ by a spray drying method to obtain the chitin nano whisker/hydroxyapatite composite material.
Step 4, 3D printing of the artificial bone material
(1) Preparing an artificial bone material: preparing 23g of chitin nano whisker/hydroxyapatite composite material;
(2) adhesive preparation: preparing 16g of polyvinyl alcohol and 200g of purified water into a polyvinyl alcohol aqueous solution with the mass fraction of 8%, placing the polyvinyl alcohol aqueous solution in a solvent bottle with a cover, heating the solution in a water bath at 95 ℃ for about 2 hours, and intermittently shaking the solution in the heating process to accelerate the dissolution of the polyvinyl alcohol to obtain a uniform solution;
(3) mixing: firstly, placing chitin nano whisker/hydroxyapatite powder and beta-tricalcium phosphate powder in a homogenizer at a mass ratio of 3:2 and mixing for 6min at a rotating speed of 1000r/min to form uniformly mixed biological ceramic powder; then mixing the uniformly mixed biological ceramic powder: the adhesives are mixed according to the mass ratio of 1:13, and the mixture is placed in a homogenizer to be mixed for 8min at the rotating speed of 1800r/min, so that the uniformly mixed slurry is formed.
(4) Three-dimensional reconstruction: the CT/MRI/X ray of the bone defect part of a patient is obtained, and a 3D printing artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure or special requirements is designed by utilizing three-dimensional reconstruction software such as Mimics research, E3D, 3matic, UG, 3D-med, slicer and the like.
(5) Printing: and printing the artificial bone by using a 3D biological ceramic printer. Firstly, filling the uniformly mixed printing slurry in the step (3) into a storage bin for high-speed centrifugal defoaming, then loading the designed artificial bone three-dimensional model STL file in the step (4) into PClab software, and setting the printing process parameters as follows: the printing speed is 10mm/s, the printing layer thickness is 150 micrometers, the average pore diameter is 450 micrometers, the slurry is uniformly extruded at a constant speed through a spiral propeller, the printing head moves along X, Y, Z directions, the printing is sequentially carried out layer by layer, and finally the printing of the customized 3D printing artificial bone is completed.
(6) And (3) freeze drying: placing the formed customized 3D printed artificial bone in the step (5) in a freeze drying box for freeze drying for 24 hours;
(7) and (3) sterilization: and (3) performing irradiation sterilization on the freeze-dried customized 3D printed artificial bone by using cobalt 60.
Example 3
Step 1, preparing colloidal chitin nano whisker
Soaking 3g of chitin in 100ml of hydrochloric acid, wherein the concentration of the hydrochloric acid is 3mol/L, placing the chitin in a triangular flask, and heating the chitin to boiling reaction for 3 hours under the stirring of mechanical force to form a colloidal product; adding water into the colloidal product to dilute the colloidal product, and uniformly stirring the mixture to form a mixed solution; centrifuging the mixed solution at 7000r/min for 8min, pouring out supernatant, and repeating the centrifuging operation; and centrifuging to obtain colloidal chitin nanowhiskers.
Step 2, removing acidic substances in the colloidal chitin nanowhiskers
Putting the chitin nano whiskers obtained in the step 1 into a dialysis bag, and performing first dialysis for 10 hours, wherein the dosage of a dialysate is 30 times that of the chitin nano whiskers, and the dialysate is deionized water; then using deionized water as dialysate to carry out second dialysis until the PH value of the dialysate is 7 and the dosage of the dialysate is 30 times of that of the chitin nano whisker to obtain colloidal chitin nano whisker suspension; and (3) freezing the chitin nano whisker suspension until the chitin nano whisker is completely frozen, and drying after freezing to finally obtain the chitin nano whisker with the average diameter of 25nm and the length of 150 nm-300 nm.
And 3, adding the chitin nanowhiskers into hydroxyapatite by an in-situ synthesis method to prepare the chitin nanowhiskers/hydroxyapatite composite material.
Adding the chitin nanowhiskers prepared in the above into 0.5mol/L Ca (NO) in an amount of 23g/L in a reaction kettle3)2In solution; opening a stirring device of the reaction kettle, setting the stirring speed to be 45r/min, and dropwise adding 0.3mol/L Na into the reaction kettle at a slower speed2HPO4Added Na2HPO4Solution with Ca (NO)3)2The volume of the solution is equal; to be treatedAnd after the addition is finished, continuously stirring until the solution is uniformly mixed to obtain a mixed solution. Then adding ammonia water into the mixed solution, adjusting the pH value of the solution to 10, heating the whole reaction system while adjusting the pH value of the solution to ensure that the reaction temperature of the reaction system is 110 ℃ to obtain a reaction system A, and continuously stirring the solution in the whole process; the reaction system A reacts in a reaction kettle for 24 hours at the reaction temperature of 110 ℃, the whole process is continuously stirred, and a process product B is obtained after the reaction. The process product B was then washed with a ceramic membrane filter to obtain a concentrated slurry. And finally, drying the concentrated slurry at 85 ℃ by a spray drying method to obtain the chitin nano whisker/hydroxyapatite composite material.
Step 4, 3D printing of the artificial bone material
(1) Preparing an artificial bone material: preparing a chitin nano whisker/hydroxyapatite composite material;
(2) adhesive preparation: preparing polyvinyl alcohol aqueous solution with the mass fraction of 10% by using polyvinyl alcohol and purified water, placing the polyvinyl alcohol aqueous solution in a solvent bottle with a cover, heating the polyvinyl alcohol aqueous solution in a water bath at 90 ℃ for about 2 hours, and intermittently shaking the solvent bottle in the heating process to accelerate the dissolution of the polyvinyl alcohol so as to obtain uniform solution;
(3) mixing: mixing the artificial bone composite material and the adhesive in a mass ratio of 1:15, and placing the mixture in a homogenizer for mixing for 7min at a rotating speed of 1600r/min to form uniformly mixed slurry.
(4) Three-dimensional reconstruction: the CT/MRI/X ray of the bone defect part of a patient is obtained, and a 3D printing artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure or special requirements is designed by utilizing three-dimensional reconstruction software such as Mimics research, E3D, 3matic, UG, 3D-med, slicer and the like.
(5) Printing: and printing the artificial bone by using a 3D biological ceramic printer. Firstly, filling the uniformly mixed printing slurry in the step (3) into a storage bin for high-speed centrifugal defoaming, then loading the designed artificial bone three-dimensional model STL file in the step (4) into PClab software, and setting the printing process parameters as follows: the printing speed is 10mm/s, the printing layer thickness is 150 micrometers, the average pore diameter is 450 micrometers, the slurry is uniformly extruded at a constant speed through a spiral propeller, the printing head moves along X, Y, Z directions, the printing is sequentially carried out layer by layer, and finally the printing of the customized 3D printing artificial bone is completed.
(6) And (3) freeze drying: placing the formed customized 3D printed artificial bone in the step (5) in a freeze drying box for freeze drying for 24 hours;
(7) and (3) sterilization: and (3) performing irradiation sterilization on the freeze-dried customized 3D printed artificial bone by using cobalt 60.
Example 4
Step 1, preparing colloidal chitin nano whisker
Soaking 4g of chitin in 100ml of hydrochloric acid, wherein the concentration of the hydrochloric acid is 3mol/L, placing the chitin in a triangular flask, and heating the chitin to boiling reaction for 3 hours under the stirring of mechanical force to form a colloidal product; adding water into the colloidal product to dilute the colloidal product, and uniformly stirring the mixture to form a mixed solution; centrifuging the mixed solution at 8000r/min for 9min, pouring out supernatant, and repeating the above centrifuging operation; and centrifuging to obtain colloidal chitin nanowhiskers.
Step 2, removing acidic substances in the colloidal chitin nanowhiskers
Putting the chitin nanowhiskers obtained in the step 1 into a dialysis bag, and carrying out primary dialysis for 11 hours, wherein the dosage of a dialysate is 40 times that of the chitin nanowhiskers, and the dialysate is tap water; then using deionized water as dialysate to carry out second dialysis until the PH value of the dialysate is 7 and the dosage of the dialysate is 40 times of that of the chitin nano whisker to obtain colloidal chitin nano whisker suspension; and (3) freezing the chitin nano whisker suspension until the chitin nano whisker is completely frozen, and drying after freezing to finally obtain the chitin nano whisker with the average diameter of 25nm and the length of 150 nm-300 nm.
And 3, adding the chitin nanowhiskers into hydroxyapatite by an in-situ synthesis method to prepare the chitin nanowhiskers/hydroxyapatite composite material.
Adding the prepared chitin nano crystal whisker into 0.5mol/L CaCl in an amount of 20g/L in a reaction kettle2In solution; the stirring device of the reaction kettle is opened, the stirring speed is set to be 50r/min,dropwise adding 0.3mol/L (NH) into the reaction kettle at a slower speed4)2HPO4Added of (NH)4)2HPO4Solution with CaCl2The volume of the solution is equal; and after the addition is finished, continuously stirring until the solution is uniformly mixed to obtain a mixed solution. Then adding ammonia water into the mixed solution, adjusting the pH value of the solution to 10, heating the whole reaction system while adjusting the pH value of the solution to ensure that the reaction temperature of the reaction system is 110 ℃ to obtain a reaction system A, and continuously stirring the solution in the whole process; the reaction system A reacts in a reaction kettle for 24 hours at the reaction temperature of 110 ℃, the whole process is continuously stirred, and a process product B is obtained after the reaction. The process product B was then washed with a ceramic membrane filter to obtain a concentrated slurry. And finally, drying the concentrated slurry at 88 ℃ by a spray drying method to obtain the chitin nano whisker/hydroxyapatite composite material.
Step 4, 3D printing of the artificial bone material
(1) Preparing an artificial bone material: preparing a chitin nano whisker/hydroxyapatite composite material;
(2) adhesive preparation: preparing a polyvinyl alcohol aqueous solution with the mass fraction of 12% by using polyvinyl alcohol and purified water, placing the polyvinyl alcohol aqueous solution in a solvent bottle with a cover, heating the polyvinyl alcohol aqueous solution in a water bath at 93 ℃ for about 2 hours, and intermittently shaking the solvent bottle in the heating process to accelerate the dissolution of the polyvinyl alcohol to obtain a uniform solution;
(3) mixing: mixing the artificial bone composite material and the adhesive in a mass ratio of 1:14, and placing the mixture in a homogenizer for mixing for 5min at a rotating speed of 2000r/min to form uniformly mixed slurry.
(4) Three-dimensional reconstruction: the CT/MRI/X ray of the bone defect part of a patient is obtained, and a 3D printing artificial bone three-dimensional model STL file suitable for a bone defect anatomical structure or special requirements is designed by utilizing three-dimensional reconstruction software such as Mimics research, E3D, 3matic, UG, 3D-med, slicer and the like.
(5) Printing: and printing the artificial bone by using a 3D biological ceramic printer. Firstly, filling the uniformly mixed printing slurry in the step (3) into a storage bin for high-speed centrifugal defoaming, then loading the designed artificial bone three-dimensional model STL file in the step (4) into PClab software, and setting the printing process parameters as follows: the printing speed is 10mm/s, the printing layer thickness is 150 micrometers, the average pore diameter is 450 micrometers, the slurry is uniformly extruded at a constant speed through a spiral propeller, the printing head moves along X, Y, Z directions, the printing is sequentially carried out layer by layer, and finally the printing of the customized 3D printing artificial bone is completed.
(6) And (3) freeze drying: placing the formed customized 3D printed artificial bone in the step (5) in a freeze drying box for freeze drying for 24 hours;
(7) and (3) sterilization: and (3) performing irradiation sterilization on the freeze-dried customized 3D printed artificial bone by using cobalt 60.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (9)

1. A preparation method of a chitin nano whisker/hydroxyapatite composite material is characterized by comprising the following steps: adding chitin nano whisker into CaCl2Solution or Ca (NO)3)2Adding (NH) while stirring to the solution4)2HPO4Solutions or Na2HPO4After the addition of the solution is finished, continuously stirring the solution until the solution is uniform to obtain a mixed solution; adding ammonia water into the mixed solution, adjusting the pH value of the mixed solution to 9-11, simultaneously heating the whole mixed solution to 100-120 ℃ to obtain a reaction system A, and reacting the reaction system A at the temperature to obtain a process product B; washing the process product B to obtain concentrated slurry, and drying the concentrated slurry to obtain the chitin nano whisker/hydroxyapatite composite material;
the reaction system A reacts for 24 hours to obtain a process product B; and drying the concentrated slurry at the temperature of 80-90 ℃ for post-treatment.
2. The method of claim 1, wherein the chitin nanowhisker and CaCl are mixed with the solution of chitin nanowhisker/hydroxyapatite2The material-liquid ratio of the solution is as follows: (15-23) g is 1L; added (NH)4)2HPO4Solution and CaCl2Equal volume of solution.
3. The method for preparing the chitin nanowhisker/hydroxyapatite composite material according to claim 1, wherein CaCl is added2The concentration of the solution was 0.5mol/L, (NH)4)2HPO4The concentration of the solution was 0.3 mol/L.
4. The method for preparing the chitin nanowhisker/hydroxyapatite composite material according to claim 1, wherein the process for preparing the chitin nanowhisker comprises the steps of: adding chitin into hydrochloric acid solution, and stirring to react to form a colloidal product; diluting and centrifuging the colloidal product to obtain colloidal chitin nanowhiskers; and dialyzing the colloidal chitin nanowhiskers to obtain chitin nanowhisker suspension, and freeze-drying to obtain the chitin nanowhiskers.
5. The method for preparing the chitin nanowhisker/hydroxyapatite composite material according to claim 4, wherein the concentration of the hydrochloric acid solution is 3mol/L, and the mixing ratio of the chitin and the hydrochloric acid solution is (2-5) g:100 mL; adding chitin into a hydrochloric acid solution, stirring and heating until boiling for reaction for 2-4 hours to form a colloidal product; adding water into the colloidal product, wherein the added water submerges the colloidal product, and stirring to form a mixed solution; centrifuging the mixed solution, and removing supernatant; adding water into the centrifugal product and repeating the centrifugal treatment to obtain colloidal chitin nano crystal whisker.
6. The method of claim 4, wherein the step of dialyzing the colloidal chitin nanowhisker comprises the steps of: putting the colloidal chitin nano whisker into a dialysis bag for first dialysis, wherein the dosage of a dialysate is 20-50 times of the volume of the chitin nano whisker, the dialysis time is 8-12 h, and the dialysate is deionized water; and after the first dialysis is finished, performing second dialysis by taking deionized water as dialysate, finishing the dialysis when the pH value of the dialysate is 7, and preparing the chitin nano whisker suspension in a dialysis bag.
7. A chitin nanowhisker/hydroxyapatite composite material prepared by the preparation method of claim 1, wherein the composite material is a composite of a chitin nanowhisker and hydroxyapatite, the chitin nanowhisker being attached to the hydroxyapatite.
8. The chitin nanowhisker/hydroxyapatite composite material according to claim 7, wherein the average diameter of the cross section of the chitin nanowhisker is 25nm, and the length of the whisker is 150nm to 300 nm.
9. The use of the chitin nanowhisker/hydroxyapatite composite material according to claim 7 in 3D printing of an artificial bone, wherein the chitin nanowhisker/hydroxyapatite composite material can be used in 3D printing of an artificial bone by mixing with an adhesive to form a mixed slurry.
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US20160038646A1 (en) * 2014-08-05 2016-02-11 The University Of Memphis Compositions and methods for enhancing healing and regeneration of bone and soft tissue
CN105504715A (en) * 2016-01-15 2016-04-20 暨南大学 Chitin whisker/magnesium oxide whisker/biodegradable polyester composite material as well as preparation method and application thereof
CN106492273A (en) * 2016-11-24 2017-03-15 暨南大学 Dual enhancing Biodegradable polyester fibrous composite of a kind of chitin whisker/chitosan nano fiber and preparation method and application
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