CN110935061A - 3D printing titanium interbody fusion cage and preparation method and application thereof - Google Patents

3D printing titanium interbody fusion cage and preparation method and application thereof Download PDF

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Publication number
CN110935061A
CN110935061A CN201911366504.4A CN201911366504A CN110935061A CN 110935061 A CN110935061 A CN 110935061A CN 201911366504 A CN201911366504 A CN 201911366504A CN 110935061 A CN110935061 A CN 110935061A
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printing
interbody fusion
cage
body structure
drug
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CN110935061B (en
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崔旭
李渊
李力韬
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8th Medical Center of PLA General Hospital
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8th Medical Center of PLA General Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/06—Titanium or titanium alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/38—Materials or treatment for tissue regeneration for reconstruction of the spine, vertebrae or intervertebral discs

Abstract

The invention relates to a 3D printing titanium interbody fusion cage and a preparation method and application thereof, wherein the 3D printing titanium interbody fusion cage comprises Ti6Al4V, a main body structure and a drug coating coated on the surface of the main body structure; the drug coating comprises a biodegradable high polymer material and an anti-infective drug. The 3D printing titanium interbody fusion cage related by the invention creatively uses Ti6Al4V material main structure surface coating containing biodegradable polymerThe interbody fusion cage has good biocompatibility, can well prevent local postoperative infection by locally releasing the drug after being implanted into a focus part, greatly reduces the incidence rate of postoperative infection, and assists interbody fusion.

Description

3D printing titanium interbody fusion cage and preparation method and application thereof
Technical Field
The invention belongs to the technical field of bone implantation materials, and particularly relates to a 3D printing titanium interbody fusion cage and a preparation method and application thereof, and particularly relates to a 3D printing titanium interbody fusion cage capable of preventing postoperative infection and a preparation method and application thereof.
Background
The infection associated with implantation is difficult to manage because it requires long-term antibiotic treatment and even revision surgery. Implants can counteract the host's immune defenses by forming biofilms, immune evasion and antibiotic resistance. Surgical Site Infections (SSIs) are one of the most serious postoperative complications. Particularly, with the introduction of the interbody fusion cage in recent years, the incidence of infection in the interbody fusion surgery has been greatly increased. Spinal surgery SSIs may be one of the most serious complications after spinal interbody fusion. The interbody fusion cage can shorten hospitalization time, relieve transplantation complications and accelerate rehabilitation, and is commonly used for maintaining the intervertebral space height and improving the bone grafting fusion rate in the spine interbody fusion operation. The intervertebral disc is a soft tissue structure that cushions interbody pressure and allows for slight movement within the spine.
The conventional interbody cage cannot prevent local postoperative infection well, cannot reduce the incidence of postoperative infection, and has poor stability of the coating attached thereto because the interbody cage requires load bearing and slight movement. Therefore, it is necessary to develop an intervertebral cage which can prevent postoperative infection and has a stable structure, and is advantageous for bone fusion.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a 3D printing titanium interbody fusion cage and a preparation method and application thereof, and particularly provides a 3D printing titanium interbody fusion cage capable of preventing postoperative infection and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the invention provides a 3D printed titanium interbody cage, the 3D printed titanium interbody cage comprising Ti6Al4V, a main body structure and a drug coating coated on the surface of the main body structure; the drug coating comprises a biodegradable high polymer material and an anti-infective drug.
The invention relates toThe 3D printing titanium interbody fusion cage creatively uses Ti6Al4The V material is coated on the surface of the main structure formed by the V material with a drug coating containing biodegradable high molecular materials and anti-infective drugs, the interbody fusion cage has good biocompatibility, can well prevent local postoperative infection by locally releasing the drugs after being implanted into a focus part, greatly reduces the incidence rate of postoperative infection, and has wide application prospect. The Ti6Al4The V host structure is prepared from Ti by conventional methods well known to those skilled in the art6Al4V is the intervertebral cage structure of the printing material.
Preferably, the main body structure is a porous main body structure, the pore diameter is 360-480 μm, for example 360 μm, 370 μm, 380 μm, 400 μm, 410 μm, 420 μm, 430 μm, 440 μm, 450 μm, 460 μm or 480 μm, and the like, and other specific values within the range can be selected, which is not described in detail herein. The porosity is 65-75%, for example, 65%, 66%, 68%, 70%, 71%, 72%, 73%, or 75%, and other specific values within the range can be selected, which is not described herein.
As a more preferable condition, the main body of the 3D printing titanium interbody fusion cage related to the invention is a porous structure, the pore diameter is specially selected to be 360-480 mu m, the porosity is specially selected to be 65-75%, and the drug coating the surface of the interbody fusion cage does not influence the porous structure. The 3D printing titanium interbody fusion cage with the specific structure has larger coatable area and increased drug loading; the medicine is more firmly attached to the coating, and the coating has better adhesion stability; more importantly, the structure is more beneficial to bone fusion and assists intervertebral fusion.
Preferably, the Ti6Al4V is Ti6Al4The particle size of the V powder is 45-105 μm, such as 45 μm, 50 μm, 60 μm, 75 μm, 85 μm, 90 μm or 105 μm, and other specific values within the range can be selected, which is not described herein.
The 3D printing titanium interbody fusion cage provided by the invention is made of Ti6Al4V powder with a particular particle size of 45105 μm, which is more favorable for the attachment of the drug and also makes the structure of the product more stable.
Preferably, the biodegradable polymer material comprises any one or a combination of at least two of polylactic acid, polylactic acid-glycolic acid copolymer, polyethylene glycol, polydioxanone, polycaprolactone or polyvinyl alcohol; the combination of at least two of the above-mentioned components, such as the combination of polylactic acid and polylactic acid-glycolic acid copolymer, the combination of polyethylene glycol and polydioxanone, the combination of polycaprolactone and polyvinyl alcohol, etc., and any other combination modes are not repeated here. Polyvinyl alcohol is preferred.
The biodegradable high polymer material and the anti-infective drug are uniformly and jointly loaded on the surface of the interbody fusion cage, and the biodegradable high polymer material can enable the drug to have a better sustained and controlled release effect.
Preferably, the number average molecular weight of the polyvinyl alcohol is 70000-80000Da, such as 70000Da, 72000Da, 74000Da, 75000Da, 76000Da, 78000Da, or 80000Da, and other specific values within the range can be selected, which is not described herein.
Preferably, the anti-infective drug comprises vancomycin hydrochloride. The invention is not limited to the type of anti-infective drug, and other anti-infective drugs other than vancomycin hydrochloride are within the scope of the invention.
Preferably, the mass ratio of the biodegradable polymer material to the anti-infective drug is 1:1-5:1, for example, 1:1, 2:1, 3:1, 4:1 or 5:1, and other specific points within the range can be selected, which is not described herein in detail.
Preferably, the loading amount of the drug coating layer on the surface of the main structure is 0.5-1.5%, for example, 0.5%, 0.6%, 0.8%, 1.0%, 1.2%, or 1.5%, etc., and other specific values within the range can be selected, which is not described herein.
In another aspect, the present invention provides a method for preparing a 3D printed titanium interbody cage as described above, the method comprising: with Ti6Al4V is used as a main material to carry out 3D printing to obtain Ti6Al4V-shaped main body knotAnd putting the 3D printing titanium interbody fusion cage into a mixed solution containing a biodegradable high polymer material and an anti-infective drug for vacuum adsorption, centrifugation and drying to obtain the 3D printing titanium interbody fusion cage.
Preferably, the obtaining Ti6Al4And blowing powder and cleaning after the V main body structure.
Preferably, the powder blowing refers to powder blowing by using high-pressure pouring powder. Meanwhile, a Powder Recovery System (PRS) is utilized, and a Powder removal is judged by using an observation method and a weight method.
Preferably, the powder blowing pressure is 4-6Bar, such as 4Bar, 4.5Bar, 5Bar, 5.5Bar or 6Bar, and other specific values within the range can be selected, which is not described in detail herein.
Preferably, the cleaning is performed by using ultrasonic waves for 30-200min, for example, 30min, 50min, 70min, 100min, 150min or 200min, and other specific point values within the range can be selected, which is not described herein.
Specifically, the cleaning is carried out for 30min by using an ultrasonic cleaning machine, then the drying is carried out for 20-30min, the cleaning is carried out for 40min by using the ultrasonic cleaning machine, then the drying is carried out for 20-30min, and the cleaning is carried out for 40min by using the ultrasonic cleaning machine, then the drying is carried out for 20-30 min.
Preferably, the mass concentration of the biodegradable polymer material in the mixed solution is 4-8%, for example, 4%, 5%, 6%, 7%, or 8%, and other specific values within the range can be selected, which is not described herein.
Preferably, the mass concentration of the anti-infection drug in the mixed solution is 2-6%, for example, 2%, 3%, 4%, 5%, or 6%, etc., and other specific values within the range can be selected, which is not described herein.
The preparation process of the mixed solution is approximately as follows: dissolving a certain amount of biodegradable high molecular material in a solvent, heating and stirring at 80 ℃ until the biodegradable high molecular material is completely dissolved to obtain a high molecular material solution, dissolving a certain amount of medicine in the solution, and stirring at room temperature until the medicine is completely dissolved to obtain the mixed solution.
Preferably, the vacuum adsorption is performed under a negative pressure of 0.1-0.2Mpa, such as 0.1Mpa, 0.12Mpa, 0.15Mpa, 0.18Mpa, or 0.2Mpa, and other specific values within the range can be selected, which is not described in detail herein.
Preferably, the vacuum-suction operation is terminated when no air bubbles are generated around the intersomatic cage.
Preferably, the centrifugation speed is 1000-2000r/min, such as 1000r/min, 1200r/min, 1500r/min, 1600r/min, 1800r/min, 2000r/min, etc., and other specific values within the range can be selected, which is not described herein again.
Preferably, the centrifugation time is 5-15min, such as 5min, 6min, 7min, 10min, 12min or 15min, and other specific values within the range can be selected, which is not described herein.
The centrifugation operation is to eliminate the excess drug solution in the cage structure.
Preferably, the drying temperature is 50-70 ℃, for example, 50 ℃, 55 ℃, 60 ℃, 65 ℃ or 70 ℃, and other specific values in the range can be selected, which is not described in detail herein.
Preferably, the 3D printing employs a metal electron beam melting technique.
Preferably, the electron beam has an output of 2-4kW, such as 2kW, 3kW or 4kW, etc., and a melting speed of 0.3-0.5m/s, such as 0.3m/s, 0.4m/s or 0.5m/s, etc.
Preferably, the printing precision of the 3D printing is ± 0.4 mm.
Preferably, the 3D printing has a delamination thickness of 0.05 mm.
As a preferred technical scheme of the present invention, the preparation method specifically comprises:
(1) obtaining a design model through UG NX6.0 software design entity and 3-matic gridding treatment, and using Ti6Al4V is a main material, and 3D printing is carried out by adopting a metal electron beam melting technology to obtain Ti6Al4A V body structure;
(2) for the Ti prepared in the step (1)6Al4The V main body structure is blown by high-pressure filling powder with the pressure of 4-6Bar, and then is blown by ultrasonic wavesCleaning for 30-200 min;
(3) ti treated in the step (2)6Al4The V main body structure is placed in an aqueous solution containing biodegradable high polymer materials and anti-infective drugs and is subjected to vacuum adsorption under the negative pressure of 0.1-0.2Mpa until no bubbles are generated around the interbody fusion cage, so that the biodegradable high polymer materials and the anti-infective drugs are coated on the surface of the main body structure;
(4) and (4) centrifuging the product obtained in the step (3) for 5-15min at the speed of 1000-.
In still another aspect, the present invention provides a use of the 3D printed titanium intervertebral cage as described above in preparing a bone implant material.
Compared with the prior art, the invention has the following beneficial effects:
the 3D printing titanium interbody fusion cage related by the invention creatively uses Ti6Al4The V material is coated on the surface of the main structure formed by the V material with a medicine coating containing biodegradable high molecular materials and anti-infective medicines, the interbody fusion cage has good biocompatibility, can well prevent local postoperative infection by locally releasing the medicines after being implanted into a focus part, greatly reduces the incidence rate of postoperative infection, and assists interbody fusion.
Drawings
FIG. 1 is an SEM photograph of products obtained in examples 1-2 and comparative example 1;
FIG. 2 is a graph showing the drug release profile of the product prepared in example 1;
FIG. 3 is a graph showing the release profile of the product prepared in example 2;
FIG. 4 is a graph of the drug release profile of the product made in example 3;
FIG. 5 is a graph showing cytotoxicity results of the product obtained in example 1;
FIG. 6 is a graph showing the results of cytotoxicity of the product obtained in example 2;
FIG. 7 is a graph showing the results of cytotoxicity of the product obtained in example 3;
FIG. 8 is a graph of in vitro bacteriostatic results;
FIG. 9 is a graph of high resolution small animal micro CT results;
FIG. 10 is a general overview of in vivo evaluation;
FIG. 11 is a graph showing the results of toluidine blue staining of hard tissue sections;
fig. 12 is a schematic view of the preparation and application process of the 3D printed titanium interbody cage according to the present invention.
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 a 3D prints titanium interbody fusion cage, 3D prints titanium interbody fusion cage includes Ti6Al4V, a main body structure and a drug coating coated on the surface of the main body structure; the drug coating comprises biodegradable high molecular material polyvinyl alcohol (with a molecular weight of 75000Da) and anti-infective drug vancomycin hydrochloride. The body has a porous structure with an average pore size of 420 μm and a porosity of 70%. Wherein the mass ratio of the polyvinyl alcohol to the vancomycin hydrochloride is 3:1, and the loading capacity of the drug coating on the main body structure is 1.0%.
The preparation method comprises the following steps:
(1) obtaining a design model through UG NX6.0 software design entity and 3-matic gridding treatment, and using Ti6Al4V is used as a main material, and 3D printing is carried out by utilizing Acram Q10 equipment and adopting a metal electron beam melting technology, wherein the output power of an electron beam is 3kW, the printing precision is +/-0.4 mm, and the layering thickness is 0.05mm to obtain Ti6Al4A V body structure;
(2) for the Ti prepared in the step (1)6Al4V, blowing powder by using high-pressure filling powder, recovering the powder by using a Powder Recovery System (PRS) System, wherein the powder blowing pressure is 5Bar, cleaning for 30min by using an ultrasonic cleaning machine, drying for 20min, cleaning for 40min by using the ultrasonic cleaning machine, drying for 30min, cleaning for 40min by using the ultrasonic cleaning machine, and drying for 30 min;
(3) ti treated in the step (2)6Al4V main bodyThe structure is placed in an aqueous solution containing polyvinyl alcohol and vancomycin hydrochloride to carry out vacuum adsorption under the negative pressure of 0.1Mpa until no bubbles are generated around the interbody fusion cage, so that the biodegradable high polymer material and the anti-infective drug are coated on the surface of the main structure; wherein the mass concentration of the polyvinyl alcohol in the solution is 6 percent, and the mass concentration of the vancomycin hydrochloride in the solution is 4 percent;
(4) and (4) centrifuging the product obtained in the step (3) for 10min at the speed of 1000r/min, and finally drying at the temperature of 60 ℃ to obtain the 3D printing titanium interbody fusion cage.
Example 2
The embodiment provides a 3D prints titanium interbody fusion cage, 3D prints titanium interbody fusion cage includes Ti6Al4V, a main body structure and a drug coating coated on the surface of the main body structure; the drug coating comprises a biodegradable high molecular material polylactic acid-glycolic acid copolymer (molecular weight 20000Da) and an anti-infective drug levofloxacin hydrochloride. The body has a porous structure with an average pore size of 400 μm and a porosity of 65%. Wherein the mass ratio of the polylactic acid-glycolic acid copolymer to the levofloxacin hydrochloride is 1:1, and the loading capacity of the drug coating on the main body structure is 0.5%.
The preparation method comprises the following steps:
(1) obtaining a design model through UG NX6.0 software design entity and 3-matic gridding treatment, and using Ti6Al4V is used as a main material, and 3D printing is carried out by utilizing Acram Q10 equipment and adopting a metal electron beam melting technology, wherein the output power of an electron beam is 4kW, the printing precision is +/-0.4 mm, and the layering thickness is 0.05mm to obtain Ti6Al4A V body structure;
(2) for the Ti prepared in the step (1)6Al4V, blowing powder by using high-pressure filling powder, recovering the powder by using a Powder Recovery System (PRS) System, wherein the powder blowing pressure is 6Bar, cleaning for 30min by using an ultrasonic cleaning machine, drying for 20min, cleaning for 40min by using the ultrasonic cleaning machine, drying for 30min, cleaning for 40min by using the ultrasonic cleaning machine, and drying for 30 min;
(3) ti treated in the step (2)6Al4V main body structure containing poly emulsionVacuum adsorbing the acid-glycolic acid copolymer and the levofloxacin hydrochloride in the water solution under 0.2Mpa negative pressure until no bubbles are generated around the interbody fusion cage, and coating the biodegradable high molecular material and the anti-infective drug on the surface of the main structure; wherein the mass concentration of the polyvinyl alcohol in the solution is 8 percent, and the mass concentration of the vancomycin hydrochloride in the solution is 5 percent;
(4) and (4) centrifuging the product obtained in the step (3) for 5min at 2000r/min, and finally drying at 60 ℃ to obtain the 3D printing titanium interbody fusion cage.
Example 3
The embodiment provides a 3D prints titanium interbody fusion cage, 3D prints titanium interbody fusion cage includes Ti6Al4V, a main body structure and a drug coating coated on the surface of the main body structure; the drug coating comprises biodegradable high molecular material polyvinyl alcohol (molecular weight of 79000Da) and anti-infective drug vancomycin hydrochloride. Wherein the mass ratio of the polyvinyl alcohol to the vancomycin hydrochloride is 5:1, and the loading capacity of the drug coating on the main body structure is 1.5%.
The preparation method comprises the following steps:
(1) obtaining a design model through UG NX6.0 software design entity and 3-matic gridding treatment, and using Ti6Al4V is a main material, and 3D printing is carried out by utilizing Acram Q10 equipment and adopting a metal electron beam melting technology, wherein the output power of an electron beam is 2kW, the printing precision is +/-0.4 mm, and the layering thickness is 0.05mm, so that Ti is obtained6Al4A V body structure;
(2) for the Ti prepared in the step (1)6Al4V, blowing powder by using high-pressure filling powder, recovering the powder by using a Powder Recovery System (PRS) System, wherein the powder blowing pressure is 4Bar, cleaning for 30min by using an ultrasonic cleaning machine, drying for 20min, cleaning for 40min by using the ultrasonic cleaning machine, drying for 30min, cleaning for 40min by using the ultrasonic cleaning machine, and drying for 30 min;
(3) ti treated in the step (2)6Al4The V main body structure is placed in an aqueous solution containing polyvinyl alcohol and vancomycin hydrochloride to carry out vacuum adsorption under the negative pressure of 0.1Mpa until no bubbles are produced around the interbody fusion cageCoating the biodegradable high molecular material and the anti-infective drug on the surface of the main structure; wherein the mass concentration of the polyvinyl alcohol in the solution is 4 percent, and the mass concentration of the vancomycin hydrochloride in the solution is 2 percent;
(4) and (4) centrifuging the product obtained in the step (3) at 1500r/min for 15min, and finally drying at 60 ℃ to obtain the 3D printing titanium interbody fusion cage.
Comparative example 1
This comparative example provides a 3D printed titanium interbody cage, the structure of which differs from the product of example 1 only in that it does not contain a drug coating, all else being identical.
The preparation method is also referred to the method in example 1.
Example 4
This example performed SEM characterization of the products of example 1 and comparative example 1, and the results are shown in FIG. 1 (where a is the product of comparative example 1 and b is the product of example 1), and b is clearly seen to have a drug coating on the outside of the main structure, and the drug coating does not change the porous structure of the cage (indicated by the arrows in the figure).
Example 5
This example examines the drug release of the 3D printed titanium interbody cage prepared in examples 1-3 by the following method: the obtained product is placed in a dialysis bag containing 2mL of PBS solution, the dialysis bag is placed in a centrifuge tube containing 5mL of PBS solution and is preserved at 37 ℃, 1mLPBS solution is removed on days 0.01, 0.02, 0.04, 0.08, 0.16, 0.32, 1, 2, 4 and 7 (1 mL of new PBS detection solution is added at the same time) to measure ultraviolet absorbance (wavelength of 280nm), and the drug concentration is calculated. Five independent measurements of released drug were made and the average was calculated. The results of the obtained drug release profiles are shown in FIGS. 2 to 4 (the abscissa of the graph is time (day)). As can be seen from the figure: the release process of the drug is a sustained and controlled release process, and the time of the drug concentration higher than 2 mug/mL is more than 7 days.
Example 6
This example examines the cytotoxicity of 3D printed titanium interbody cages prepared in examples 1-3 and comparative example 1 as follows: using mouse osteogenic precursor cells (MC3T3-E1)And performing cytotoxicity evaluation, and respectively dividing the cell into a mouse osteogenesis precursor cell culture group, a mouse osteogenesis precursor cell and uncoated titanium interbody fusion cage (comparative example 1) co-incubation group and a mouse osteogenesis precursor cell and drug coated titanium interbody fusion cage co-incubation group. Cells were cultured in basal Medium (DMEM) containing 20% fetal bovine serum in 5% CO2Incubate at 37 ℃ for 7 days at ambient temperature. After the cells were fused, they were transferred into a test tube for concentration. Then, the cells were counted and the concentration was adjusted to 6X 104and/mL. Cells were transferred to 96 well cell culture plates, each well containing 1mL of cells. These dishes were then placed in an incubator at 37 ℃ containing 5% carbon dioxide. When the cells were adhered to the plate, each set of the intersomatic cages was put into 5 wells, respectively. All interbody cages were removed after 1 or 3 days. The medium was removed and CCK-8 solution diluted 1:9 by volume of medium was added. Finally, the absorbance of the sample at 450nm was tested using a multimode microplate detection system (EnSpireTM, PE, USA). Background absorbance was measured at 650nm using 90mL DMEM and 10mL CCK-8.
The results are shown in FIGS. 5 to 7 (in the figures, the abscissa represents the time (day)). As can be seen from the figure: the cells treated with the titanium intersomatic cage with the drug-coated structure and the titanium intersomatic cage without the drug-coated structure showed high cell survival rate. These results indicate that the 3D printed titanium intervertebral fusion device according to the present invention has good biocompatibility.
Example 7
In this embodiment, the in-vitro antibacterial condition of the 3D-printed titanium intervertebral fusion body prepared in example 1 and comparative example 1 is examined by the following method: two sets of bracket channels Co60And (5) sterilizing and storing. Respectively selecting staphylococcus aureus, staphylococcus epidermidis and escherichia coli colonies, fully grinding the staphylococcus aureus, staphylococcus epidermidis and escherichia coli colonies, placing the ground staphylococcus epidermidis and escherichia coli colonies into a PBS buffer solution, and stirring the mixture by using a high-speed stirrer. The highest ultraviolet absorption peak at 600nm is measured to be 0.1 by utilizing an ultraviolet spectrophotometer to determine that the concentration of the bacterial suspension is 1 multiplied by 108CFU/mL, 0.1mL of the bacterial suspension at this concentration was uniformly spread on a Roche dish, and two sets of the scaffolds were placed in the center of the dish, and after 1 week and 2 weeks, respectively, at 37 deg.C, the results were as shown in FIG. 8 (in which a1-a3 are comparative examples in this order)1 the product is placed in the escherichia coli colony, staphylococcus aureus and staphylococcus epidermidis for 2 weeks; b1-b3 show the condition of the product of example 1 after being placed in the colonies of Escherichia coli, Staphylococcus aureus and Staphylococcus epidermidis for 1 week in sequence; c1-c3 are for 2 weeks after the product of example 1 is placed in colonies of Escherichia coli, Staphylococcus aureus and Staphylococcus epidermidis).
As can be seen from the figure, the 3D-printed titanium interbody fusion cage prepared in comparative example 1 has a poor bacteriostatic effect on the three bacteria, and the 3D-printed titanium interbody fusion cage prepared in example 1 has a very significant in-vitro bacteriostatic effect (especially on staphylococcus aureus and staphylococcus epidermidis).
Example 8
This example examines the animal experimental conditions of the 3D printed titanium interbody cage prepared in example 1 and comparative example 1, as follows: new Zealand rabbits, aged 21 weeks and weighing 2.5-3.0 kg, are provided by the eighth medical center of the general Chinese people Release military Hospital. All treatments were ethical to the animals.
New Zealand rabbits were randomly divided into two groups. Drilling artificial bone defect (cylinder, D0.60 cm, h 0.80cm) on femoral condyle, and adding gelatin sponge to the bone with a volume of 1 × 1060.1mL of the bacterial suspension of CFU was implanted into the defect site. The product of comparative example 1 was implanted into a bone defect site of a new zealand rabbit as a control group, and the product of example 1 was used as an experimental group. The fascia was then closed with 3/0 sutures and the skin was closed with 4/0 sutures. Animals were sacrificed at 1, 4, and 7 weeks, respectively, and femoral condyle specimens were tested for bone mineral density and morphological changes using high resolution small animal micro ct (micro-computed tomogry). Toluidine Blue Staining (TBS) was performed 1, 4, 7 weeks post-surgery to assess the degree of inflammation and bone repair.
The results of the high resolution mini-CT of the small animals are shown in FIG. 9 (wherein a1-a3 are sagittal, transverse and coronal maps of the product of comparative example 1 after being implanted into the new zealand rabbit bone defect site for 1 week, b1-b3 are sagittal, transverse and coronal maps of the product of example 1 after being implanted into the new zealand rabbit bone defect site for 1 week, c1-c3 are sagittal, transverse and coronal maps of the product of example 1 after being implanted into the new zealand rabbit bone defect site for 4 weeks, and d1-d3 are sagittal, transverse and coronal maps of the product of example 1 after being implanted into the new zealand rabbit bone defect site for 7 weeks): after 1 week of operation, the results clearly show that there is severe trabecular bone destruction and extensive bone defect around the titanium cages of the control group, the bone damage caused by infection is increased, and the titanium cages slip out of the bone defect parts. Whereas the experimental group showed only a decrease in bone mineral density and a lower degree of bone destruction in the vicinity of the cage at weeks 1, 4 and 7 after the operation, and bone fusion around the cage occurred at week 7 (the dotted line region in the figure is the defect).
The general view is shown in fig. 10 (a is the view after the product of comparative example 1 is implanted into the bone defect site of a new zealand rabbit for 1 week, b is the view after the product of example 1 is implanted into the bone defect site of the new zealand rabbit for 1 week, c is the view after the product of example 1 is implanted into the bone defect site of the new zealand rabbit for 4 weeks, and d is the view after the product of example 1 is implanted into the bone defect site of the new zealand rabbit for 7 weeks). As can be seen from the figure: the 3D printing titanium interbody fusion cage prepared in the comparative example 1 has poor effect due to 1 week surface pus overflowing after being locally implanted, the 3D printing titanium interbody fusion cage prepared in the example 1 has the effect of inhibiting infection phenomenon 1 week after being locally implanted, and the healing result of the implanted part is very obvious along with the prolonging of time.
Toluidine Blue Staining (TBS) hard tissue sections are shown in FIG. 11 (a1, b1, c1, d1 are 4-fold enlarged graphs after 1 week of implantation for the comparative example 1 product, 1 week, 4 weeks, 7 weeks for the example 1 product, a2, b2, c2, d2 are 40-fold enlarged graphs after 1 week of implantation for the comparative example 1 product, 1 week, 4 weeks, 7 weeks for the example 1 product, respectively). As can be seen from the figure: inflammatory cell infiltration and necrosis were observed in both the control and experimental groups. These results confirm that both groups are infected with staphylococcus aureus. In addition, trabecular fractures occurred 1 week postoperatively in both groups, and a small amount of bone debris was present. However, at 4 weeks post-surgery, the experimental group showed a significant reduction in inflammatory cell infiltration and a discrete fibrocystic formation in the interbody cage and surrounding bone tissue. After 7 weeks of operation, the bone fragments of the experimental group are reduced, the infiltration of inflammatory cells is greatly reduced, and in addition, the discontinuous fibrous capsule thickness between the trabecular bone and the intervertebral fusion device of the experimental group is obviously increased. The pathological results show that the interbody fusion cage can effectively inhibit SSIs-related inflammatory changes caused by staphylococcus aureus (in the figure, black solid arrows represent inflammatory cells, black dotted arrows represent broken bone blocks, white solid arrows represent fibrous capsules, white dotted arrows represent necrotic inflammatory cells, and solid rectangular areas are visual field areas of a2, b2, c2 and d2 respectively).
The applicant states that the present invention is described by the above embodiments of the present invention, but the present invention is not limited to the above embodiments, i.e. it does not mean that the present invention must be implemented by the above embodiments. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

Claims (10)

1. The 3D printing titanium interbody fusion cage is characterized in that the 3D printing titanium interbody fusion cage comprises Ti6Al4V, a main body structure and a drug coating coated on the surface of the main body structure; the drug coating comprises a biodegradable high polymer material and an anti-infective drug.
2. The 3D printing titanium interbody fusion cage of claim 1, wherein the body structure is a porous body structure, the pore size is 360-480 μm, and the porosity is 65-75%;
preferably, the Ti6Al4V is Ti6Al4V powder with a particle size of 45-105 μm.
3. The 3D printing titanium interbody fusion cage of claim 1 or 2, wherein the biodegradable polymer material comprises any one or a combination of at least two of polylactic acid, polylactic acid-glycolic acid copolymer, polyethylene glycol, polydioxanone, polycaprolactone, or polyvinyl alcohol; preferably polyvinyl alcohol;
preferably, the number average molecular weight of the polyvinyl alcohol is 70000-80000 Da;
preferably, the anti-infective drug comprises vancomycin hydrochloride.
4. The 3D-printed titanium interbody cage of any one of claims 1-3, wherein the mass ratio of the biodegradable polymer material to the anti-infective drug is 1:1-5: 1;
preferably, the loading rate of the drug coating on the surface of the main structure is 0.5% -1.5%.
5. The method of preparing a 3D printed titanium interbody cage of any of claims 1-4, wherein the method of preparing comprises: with Ti6Al4V is used as a main material to carry out 3D printing to obtain Ti6Al4And the V main body structure is placed in a mixed solution containing a biodegradable high polymer material and an anti-infective drug for vacuum adsorption, centrifugation and drying to obtain the 3D printing titanium interbody fusion cage.
6. The method of preparing a 3D printed titanium interbody cage of claim 5, wherein the obtaining Ti is performed6Al4Blowing powder and cleaning are carried out after the V main body structure;
preferably, the powder blowing refers to powder blowing by using high-pressure pouring powder;
preferably, the powder blowing pressure is 4-6 Bar;
preferably, the cleaning is performed for 30-200min by using ultrasonic waves.
7. The method for preparing the 3D printing titanium interbody fusion cage as claimed in claim 5 or 6, wherein the mass concentration of the biodegradable polymer material in the mixed solution is 4-8%;
preferably, the mass concentration of the anti-infection drug in the mixed solution is 2-6%;
preferably, the vacuum adsorption is carried out under the negative pressure of 0.1-0.2 Mpa;
preferably, the vacuum adsorption operation is ended when no air bubbles are generated around the interbody cage;
preferably, the speed of the centrifugation is 1000-;
preferably, the time of centrifugation is 5-15 min;
preferably, the temperature of the drying is 50-70 ℃.
8. The method for preparing a 3D printed titanium interbody cage of any of claims 5-7, wherein the 3D printing employs a metal electron beam melting technique;
preferably, the output power of the electron beam is 2-4kW, and the melting speed is 0.3-0.5 m/s;
preferably, the printing precision of the 3D printing is ± 0.4 mm;
preferably, the 3D printing has a delamination thickness of 0.05 mm.
9. The method for preparing a 3D-printed titanium interbody cage according to any of claims 5 to 8, wherein the method specifically comprises:
(1) obtaining a design model through UG NX6.0 software design entity and 3-matic gridding treatment, and using Ti6Al4V is a main material, and 3D printing is carried out by adopting a metal electron beam melting technology to obtain Ti6Al4A V body structure;
(2) for the Ti prepared in the step (1)6Al4The V main body structure is subjected to powder blowing by filling powder at high pressure, the powder blowing pressure is 4-6Bar, and then ultrasonic cleaning is carried out30-200min；
(3) Ti treated in the step (2)6Al4The V main body structure is placed in an aqueous solution containing biodegradable high polymer materials and anti-infective drugs and is subjected to vacuum adsorption under the negative pressure of 0.1-0.2Mpa until no bubbles are generated around the interbody fusion cage, so that the biodegradable high polymer materials and the anti-infective drugs are coated on the surface of the main body structure;
(4) and (4) centrifuging the product obtained in the step (3) for 5-15min at the speed of 1000-.
10. Use of the 3D printed titanium intervertebral cage according to any of claims 1-4 for the preparation of bone implant materials.
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