CN109701080A - 4 axis 3D printing tubular medical brackets of one kind and preparation method thereof - Google Patents
4 axis 3D printing tubular medical brackets of one kind and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
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- 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
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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
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/222—Gelatin
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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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
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- A—HUMAN NECESSITIES
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- 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
- A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y10/00—Processes of additive manufacturing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/22—Materials or treatment for tissue regeneration for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus
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Abstract
本发明涉及一种4轴3D打印管状医用支架及其制备方法和应用，包括具有多级孔隙结构的管状支架，纳米纤维包覆在支架表面形成双层管状支架，用于管状组织修复、血管外支架和人工气管支架等。本发明解决了挤出式特别是熔融沉积成型(FDM)3D打印难以直接构建多孔管状支架的问题，所制备的医用支架在结构上具有精确可控的多级孔隙结构，方法简单、快捷、适用于多种材料，在修复管状组织和器官包括血管、气管、食道、尿道等方面具有良好的应用前景。
The invention relates to a 4-axis 3D printing tubular medical stent, a preparation method and application thereof, including a tubular stent with a multi-level pore structure. Nanofibers are coated on the surface of the stent to form a double-layer tubular stent, which is used for tubular tissue repair, extravascular Stents and artificial tracheal stents, etc. The invention solves the problem that it is difficult to directly construct a porous tubular stent by extrusion, especially by fused deposition modeling (FDM) 3D printing. The prepared medical stent has an accurate and controllable multi-level pore structure in structure, and the method is simple, fast and applicable. It has good application prospects in repairing tubular tissues and organs including blood vessels, trachea, esophagus, urethra, etc.
Description
Technical field
The invention belongs to Medical rack field, in particular to a kind of 4 axis 3D printing tubular medical brackets and preparation method thereof.
Background technique
Organizational project is related to as an interdisciplinary fields, the basic principle of integrated application engineering science and life science
A series of mixing together of subjects such as clinical medicine, biomaterial, cell biology, bioengineering, purpose are mainly ground
Exploitation is studied carefully for repairing, and is maintained, or improve the substitute with physiological function of human body disease damage tissue.There are a large amount of pipes in human body
Tissue or organ such as blood vessel, tracheae, esophagus, enteron aisle, urethra of shape structure etc. rise in maintaining human normal physiological activity
Important role is arrived, the lesion of these tubular tissues, which will lead to, greatly injures even death to human body.In global range, the heart
Vascular diseases are to cause dead one of principal element, are only second to cancer.The cause of disease is mainly since coronary artery blockage causes blood
It flows unsmooth, causes cardiac muscular tissue's nutrition supply insufficient and myocardial infarction occurs.Tracheae, oesophagus because the factors such as tumour, physics and chemistry cause it is narrow
Narrow influence tracheae function and must not all right trachea resection rebuild, surgical resection therapy exist transfinite excision after direct anastomosis difficult etc.
Problem.It is therefore current that clinically there is an urgent need to a large amount of tubular brackets to carry out coronary bypass hand as artificial blood vessel
Art and artificial trachea or artificial esophagus carry out the substitution of defect and coincide.
Ideal tubular tissue engineering rack should have the micro of suitable cell Growth and Differentiation；With it is open,
Interconnected microcellular structure, to promote the release of cytotrophy substance diffusion and metabolite；With suitable mechanical strength
And airtightness, to substitute physiological function necessary to tubular tissue；With controllable biological degradability, it is desirable that degradation rate and
The rate of regeneration matches, and biological support is gradually degraded finally to be metabolized and be excreted while regeneration.However mesh
Before can really be applied in clinical artificial tubular graft, the overwhelming majority be all using terylene, silica gel, polytetrafluoroethylene (PTFE) this
Class inert polymer material mainly prepares tubular structure by fibrage method.But this kind of graft lacks biology and lives
Property, it is permanently implanted in the body as substitution foreign matter；The method for being processed into tubulose is complicated, needs first to be prepared into fiber and arrives special mould again
It carries out being compiled into type on tool；It is more demanding to the selectivity of material, it is only applicable to some materials.Therefore, how one kind is developed
Open method can be suitable for multifarious biomaterial, and can quick, controllable precise the tubulose for obtaining sizes
Medical rack is necessary.
3D printing technique (also known as 3D rapid shaping technique or RP) is used as a kind of novel digital forming technique, passes through material
The increasing material manufacturing mode accurately accumulated, can quickly manufacture stereochemical structure.It is patient personalized fixed that having in the medical field meets
System and the precisely advantages such as medical treatment, and show great application prospect.Current 3D printing technique is substantially based on spray head peace
Platform is in the movement in tri- directions X/Y/Z, and material is piled into manufacture stereochemical structure under the effect of gravity.This structure generally has
There are outer dimension corresponding with disease damage model and porous structure, is applied well in terms of orthopaedics and plastic surgery.But
It is to have the particular/special requirement of thin-walled porous structure due to tubular bracket, and the forming principle of piling up of 3D printing needs it using branch
Support structure causes the 3D printing method for being difficult with extrusion molding directly to prepare tubular bracket.
Generally speaking, human body pipe tissue defect and reparation are in great demand, and existing artificial tubular graft is big
Mostly inertia long-term substitute lacks bioactivity.Material and rack forming method are that two of tubular bracket preparation are critical to
Element, there is also very big defects on printing thin-walled porous tubular scaffolds at present for 3D printing technique.
Coronary Artery Bypass Grafting is one of current treatment coronary heart disease most efficient method, which passes through vasotransplantation
The blood fortune for repairing or rebuilding obstruction coronary artery, improves myocardial ischemia, improves patients ' life quality.Great saphenous vein is clinical most common
Graft, but compared compared with arterial grafts such as internal mammary artery, radial arterys, the long-term patency rate of vein grafts is lower, main former
Because being implanted into early stage thrombosis, middle and later periods endometrial hyperplasia and atherosclerosis plaque forming.Which has limited the clinical applications of vein plant.
Clinical at present there are many methods for preventing vein graft restenosis, such as use anticoagulant, antiplatelet drug, statins
Object obtains vein etc. using no-touch technology in art.It is worth noting that, researcher is constantly exploring in the past few decades
With the clinical application of research External stent.Originally, External stent is intended to limit phlebectasia, maintains vein graft and target blood
The internal diameter consistency of pipe stablizes haemodynamics, reduces turbulent flow, antithrombotic.Then studies have found that, using blood vessel outside
Bracket not only can be with antithrombotic, and can reduce vein graft endometrial hyperplasia, improves long-term patency rate, so that propping up outside blood vessel
Frame is used widely and is developed.Material for making bracket constantly develops into metal material, life from early stage Teflon fiber
Biodegradable high molecular material.But External stent has no breakthrough in recent years, or even has research to claim External stent
Remarkable effect is had no in terms of preventing vein graft restenosis, this undoubtedly limits the clinical application of External stent.Thunder pa is mould
Element is macrolide antibiotics, can inhibit vascellum endometrial hyperplasia by combining mTOR receptor to inhibit smooth muscle cell proliferation, prevent
Only restenosis of vein.Aspirin is non-steroid anti-inflammatory drug, by inactivating Cycloxygenase, inhibits platelet aggregation, is to face
The most common antiplatelet drug of bed.We have made a kind of biodegradable blood of PCL- rapamycin using 3D printing technique
Pipe support arm, wraps vein grafts using support arm, discharges drug by scaffold degradation, reaches and inhibit vascellum endometrial hyperplasia
Purpose；It in conjunction with the mechanical support that timbering material provides, prevents vein from distorting, stablizes haemodynamics, reduce turbulent flow, reaching prevents
The purpose of vein graft restenosis.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of 4 axis 3D printing tubular medical brackets and preparation method thereof,
It solves extruded type 3D printing to be difficult to prepare the root problem of thin-walled porous tubular scaffolds, prepared Medical rack is in structure
Multistage pore structure with controllable precise, there is excellent elasticity and a suture property in mechanical property, method is simple, it is quick,
Suitable for a variety of biomaterials, have a good application prospect.
The present invention provides a kind of 4 axis 3D printing tubular medical brackets, the tubulose bullet including nanofiber and 4 axis 3D printings
Spring bracket, nano fiber coated form double-layer structure in rack surface；Multistage pore structure includes lines in sleeve bracket
Hole that shape material interweaves, the micropore or nano-pore and nanofiber for being uniformly distributed and being interconnected in wire member are heavy
The nanoaperture structure for accumulating, wrapping, be interweaved and being formed.
The present invention also provides a kind of preparation methods of 4 axis 3D printing tubular medical brackets, comprising:
(1) gel like material, thermoplastic material or thermosetting material are mixed with packing material 1:0.5-3 in mass ratio
For obtained composite material as ink material, being squeezed out ink material by 3D printing is in linear；Using rotating device as connecing
It is closed flat platform, the two cooperates to form the 4 axis formation systems of X/Y/Z/Rotation, obtains the tubulose branch with spring structure
Frame；
(2) tubular bracket with spring structure is subjected to solidification crosslinking, removes packing material then to get with micropore
Or the sleeve bracket of nano-pore structure；
(3) the sleeve branch that step (2) obtains is placed on rotating device or there is bullet by what step (1) obtained
The tubular bracket of spring structure is placed directly on rotating device without step (2), passes through electrostatic spinning as receiving platform reception
It is formed by nanofiber, makes nano fiber coated in rack surface to get 4 axis 3D printing tubular medical brackets.
Gel like material in the step (1) is polyacrylamide, sodium alginate, collagen, gelatin or fibroin；Thermoplastic
Property material be polycaprolactone, polylactic acid, poly lactide-glycolide acid or thermoplastic polyurethane；Thermosetting material is poly-
Decanedioic acid glyceride, heat-curable urethane or epoxy resin.
Packing material in the step (1) is salt particle, graphene, carbon nanotube, bio-vitric, silica, nothing
Machine ceramic-like materials, nano clay, nano short fiber (the short fibre of such as carbon fiber), biotic factor or drug.
Hybrid mode in the step (1) is solvent mixing method or heating.
The technological parameter of 3D printing in the step (1) are as follows: extrusion chamber temperature and nozzle temperature be 0~250 DEG C (preferably
100~200 DEG C), setting XY axis movement velocity is 0.1~20mm/s, and T axis material extrusion speed is 0.008-0.1mm/s, reception device
5~150r/min of rotation speed, receiver diameter are 2~20mm, and receiver cross sectional shape is round, oval, triangle or four
Side shape.
Solidification crosslinking in the step (2) is heat cross-linking, photo-crosslinking or other modes crosslinking.
The pore-size distribution of sleeve bracket in the step (2) is 10 nanometers to 100 microns.
Electrostatic spinning process parameter in the step (3) are as follows: polymer solution concentration: 6-15% (w/v), high-voltage electricity
: 8-15kV gives liquid speed rate: 0.6-1.5mL/h, the rotation speed of rotating device: 20-1500r/min.
The diameter of extrusion line strip material can squeeze out the state modulators such as pressure by nozzle diameter in the step (1)；Spray
Mouth printing movement speed and receiving platform the adjustable matching of rotation speed, with control fibrous material intertexture density and
Pore size；Pipe thickness can be controlled by the print time；Caliber size can be controlled by the size of receiver；Pipe
Cross sectional shape can be controlled by receiver shape.
Curing degree can be controlled by condition of cure and curing time in the step (2), to obtain different mechanics
The thermosetting property sleeve bracket of feature and performance.
Micropore or nano-pore are evenly distributed in linear material in the step (2), and size depends on making
With the dimensions of removable packing material.The partial size of packing material is typically chosen 10nm-50 μm.
In the step (3) Electrospun nano-fibers can even compact be coated on sleeve bracket and form the double-deck knot
The tubular bracket of structure；Material, pattern, diameter, the nanoporous structure of outer layer nanofiber can be adjusted by spinning parameter
Section；The thickness of outer layer nanofiber is controlled by the spinning time；The orientation of outer layer nanofiber is by adjusting receiver rotation
Rotary speed is controlled.
The present invention also provides a kind of applications of 4 axis 3D printing tubular medical brackets to be used as in conjunction with related drugs or the factor
Tracheae regeneration biological bracket.
The present invention also provides a kind of applications of 4 axis 3D printing tubular medical brackets, in conjunction with antiplatelet or anticoagulation
Object, the External stent as coronary bypass medium sized vein graft.Phlebectasia can be limited, vein graft and target are maintained
The internal diameter consistency of blood vessel reduces vein graft inner membrance and increases, raw to stablize haemodynamics, reduces turbulent flow, antithrombotic mentions
High long-term patency rate.
Using PGS as the material of internal layer biology spring, salt particle as packing material, collagen as outer layer nanofiber material
Illustrate the principle of the present invention for material:
Salt particle is smashed with pulverizer, sieve screens the salt particle within the scope of certain size, by salt particle and PGS prepolymer
It is mixed in different ratios, melts the printability in printing experiment in practical 3D by investigating composite material, including extrudability
With the conformality in the stability and subsequent high temperature solidification process of initial configuration, the most suitable mixed proportion of comprehensive selection with
Meet the requirements of PGS composite material 3D printing.By mixture mounted in 3D printing in syringe, ideal print parameters are adjusted,
It is required that can continuous uniform fiber squeeze out (good extrudability), have good initial configuration stability after the completion of printing.
For the PGS tubulose biology spring of internal layer, multi-level pore structure is devised.Pass through the printing speed to 3D printing
It spends and to jointly control and cooperate with rotary receiving platform.So that PGS prepolymer composite material is squeezed out with linear and is in
Uniform spiral shape deposits on Rotation of receiver axis, is back and forth twice afterwards in fiber interweaving shape porous structure.Further formed after solidification
Stablize chemistry cross-linked structure, forms stable binding site between the fiber of intertexture, it is water-soluble except being formed in internal stent after salt grain
Even distribution and interconnected micropore.Biological spring after forming can be controlled by using the receiver of different shape and specification
Outline shape；The diameter for squeezing out lines can be adjusted by using different size nozzle；Convenient adjusting material extrusion line can be passed through
The ratio of speed and receiving axis linear velocity or the reciprocal time of printing control intertexture density；It can be made by adjusting salt grain
The porosity and pore size for being distributed in material internal micropore are controlled with ratio and size.It is final to obtain to intertexture density, hand over
Knit hole, the high tubulose biology spring of distribution these character control degree of micropore in lines.
Above-mentioned biological spring is placed on metal rotation recipient, is prepared into gelatin solution using electrostatic spinning technique
Even nanofiber, and adsorb and surround biological spring surface, form fine and close outer layer nanofibrous structures.The microcosmic shape of fiber
Looks such as diameter can be controlled easily by spinning parameter；The distribution of fiber can be by adjusting receiver rotation speed
Controlled (high speed rotation can get orientation nanofiber)；The thickness of fibrous layer can be controlled by the spinning time.It spins
Silk is completed obtained double-layer scaffold and is handled by glutaraldehyde solution, so that stable chemical crosslinking occurs for outer gelatin；Outside gelatin
Layer dimensional contraction may consequently contribute to ectonexine and closely combine.It is final to obtain 4 axis 3D printing tubular medical brackets.Then it is freezed
The moisture in bracket is dried and removed, in order to use and long-term preservation.
The present invention is with poly- decanedioic acid glyceride (PGS) bioelastic of the thermosetting property being widely used in field of tissue engineering technology
For body, gelatin, assisted by Fused Deposition Modeling (FDM) this 3D printing technique and Rotation of receiver platform
With work, the 4 axis print systems of X/Y/Z/Rotation are formed, to prepare perforated tubular biology spring, and combine electrostatic spinning
The building of technology realization two-layer compound tubulose bracket.The bilayer that this internal layer is 3D printing biology spring, outer layer is nanofiber
Tubular bracket is at present still without report.
Beneficial effect
(1) present invention solves extruded type 3D printing and is difficult to prepare the root problem of thin-walled porous tubular scaffolds, prepared
Tubular medical bracket there is the multistage pore structure of controllable precise, method is simple, it is quick, be suitable for a variety of biomaterials, can
According to the data such as the CT of patient carry out personalized customization needed for Medical rack, can be used for preparing artificial blood vessel, tracheae, oesophagus,
Tubular bracket needed for urethra and other organizational projects, has a good application prospect；
(2) present invention is made using 3D printing technique on previous Research foundation and carries medicine External stent, for preventing hat
Shape artery bypass grafting Postoperative Intravenous graft thrombosis, intimal hyperplasia of vein graft prevent buckling of vessel, improve vein and move
Plant long-term patency rate.
Detailed description of the invention
Fig. 1 is the process flow diagram of embodiment；
Fig. 2 is the double-layer structure of tubular bracket and the schematic diagram of multistage microcellular structure；
Fig. 3 is the pictorial diagram of 3D printing PGS tubulose biology spring crosslinking front and back, double layered tubular bracket pictorial diagram；
Fig. 4 is the surface electron microscope of PGS tubulose biology spring；
Fig. 5 is the section electron microscope of PGS tubulose biology spring；
Fig. 6 is the electron microscope of outer layer gelatine nano fiber in double layered tubular bracket；
Fig. 7 is that the circulation Compressive Mechanical of double layered tubular elastic support is tested；
Fig. 8 is to plant cartilage cell outside double layered tubular support body and cultivate the live-dead dyeing one day after, after four days
(a, b), Apoptosis dye (c, d) and DNA quantitative analysis (e)；
Fig. 9 is the histological stain of sample slice after planting cartilage cell 8 weeks outside double layered tubular support body；Wherein, a-b weight
Build tubulose cartilage pictorial diagram, c-f be respectively hematoxylin eosin staining (hematoxylin-eosin staining, HE), kind
Red fast green dyeing (Safranin-O), masson and Type Ⅱ collagen dyeing；
Figure 10 be the outer repopulating cell culture of double layered tubular support body after two weeks, after being further implanted to nude mice by subcutaneous 12 weeks
Immunohistochemistry and various regenerating bone or cartilages feature evaluation；Wherein, a-d is respectively hematoxylin eosin staining
(hematoxylin-eosin staining, HE), the fast green dyeing (Safranin-O) of sarranine, masson and Type Ⅱ collagen dye
Color；E-j is Acellular matrix implant, the weight in wet base of load cells stent implant and normal cartilage, thickness, Young's modulus, DNA
The quantitative analysis comparison of content, GAG content, collagen content；
Figure 11 is the PCL tubular bracket of different shape structure；Wherein, a, b are the round tubular bracket of different-diameter, c, d
For the electron microscope (surface and section view) of tubular bracket, e-h is illustraton of model, pictorial diagram and the electron microscope of triangle tubulose bracket
(surface and section), i-l are illustraton of model, pictorial diagram and the electron microscope (surface and section) of hexagon tubular bracket；
Figure 12 is the PCL tubular bracket of diverse microcosmic structure；Wherein, a is the illustraton of model of 4 axis printing, and b is that tubular bracket is fine
Tie up interweave illustraton of model, c be different interleaving density tubular bracket pictorial diagram, d-g be in the case where controlling other parameters permanence condition,
It obtains the electron microscope of different interleaving density tubular bracket by controlling recipient revolving speed (revolving speed is respectively 10r/min, 20r/
Min, 30 r/min, 40r/min)；
Figure 13 is the correlation curve of theoretical model curves and experimental data；A is the spiral spacing experiment for printing single fiber
The comparison of curve and theoretical curve, b are the comparison of the empirical curve and theoretical curve of parallel fibers spacing in pilotaxitic texture, and c is
The comparison of the empirical curve and theoretical curve of fibre diameter, d are the empirical curve of fiber interweaving angle and theory in pilotaxitic texture
The comparison of curve；
Figure 14 is External stent zoopery operation schematic diagram；
Figure 15 schemes surely for ultrasonic flow speed after External stent implantation.
Specific embodiment
Below with thermosetting polymer PGS and thermoplastic polymer polycaprolactone (PCL) for representative, in conjunction with specific implementation
Example, the present invention is further explained.It should be understood that these embodiments are merely to illustrate the present invention rather than limit model of the invention
It encloses.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art can make various change to the present invention
Dynamic or modification, these equivalent forms also fall within the scope of the appended claims of the present application.
1. preparation process
1.1 printed materials prepare
The hybrid parameter of PGS prepolymer (Pre-PGS) and salt particle directly determines extrudability, initial when bracket prints
The pore structure of morphological stability, hot setting conformality and bracket, to determine the performance of bracket, including mechanical property indirectly
Energy and biological degradability.10g Pre-PGS is dissolved in 10ml acetone and forms thick solution；NaCl is placed in pulverizer and crushes it
Afterwards, salt grain of the diameter less than 38 μm is sieved to obtain by sieve；20g is added with Pre-PGS 1:2 in mass ratio in salt grain to be uniformly mixed,
Standing is placed in vacuum drying oven 30 DEG C after slightly volatilizing to acetone, removes acetone for 24 hours；
The tubular structure of 1.2 3D printing Pre-PGS fiber interweavings
The mixing material of Pre-PGS and NaCl particle is put into barrel.Extrusion chamber temperature is set and nozzle temperature is 45
℃.23G syringe needle is selected, print length is 6 centimetres.Setting XY axis movement velocity is 0.1mm/s, and T axis material extrusion speed is
0.008mm/s.Diameter is selected to be installed to rotatable receive on platform as receiver for the stainless steel round bar of 5mm.It regulates
Spray head is 3mm, speed of rotation 10r/min at a distance from receiver.Composite material squeezes out in linear and is deposited on pole table
Face goes out helical structure in pole printout surface with the movement of spray head, and reciprocal printing forms porous twice (or repeatedly)
The tubular structure of fiber interweaving.
1.3 Pre-PGS biology springs solidify crosslinking and the precipitation of packing material
The tubular structure of above-mentioned Pre-PGS fiber interweaving is placed in 100 DEG C of vacuum drying oven, 0.5bar together with metal bar together
Vacuum degree primary solidification 12 hours, be then adjusted to 150 DEG C, 1bar vacuum degree continue solidification 24 hours.It is stable to obtain
It is chemically crosslinked structure, while the position that fiber is interlaced with one another forms stable binding site.For remove bracket in salt particle and
Bracket is immersed in the solution that distilled water is mixed in 1:3 ratio at room temperature, changes within every 4 hours by uncrosslinked polymer
Once, it washs 3 times, after freezing 12 hours, is placed in -20 DEG C, freeze-drying obtains porous tubulose in the freeze drier of 50Pa
PGS biology spring.
The preparation of 1.4 double layered tubular brackets
It configures gelatin/hexafluoroisopropanol solution (12%, w/v) and is used as electrostatic spinning solution, be pumped into the syringe of 5ml,
And it is mounted on micro-injection pump.Above described tubular PGS biology spring is penetrated on the metallic receptor of dimension, is installed to
On the Rotation of receiver device of adjustable-speed.It is 1ml/h in injection rate, forms uniformly continuous under the action of 12KV high-pressure electrostatic
Rotation of receiver device is put into below Static Spinning syringe needle at 15cm, with the rate Rotation of receiver of 30r/min, nanometer by nanofiber
Fiber is deposited by electrostatic adsorption and surrounds PGS tubulose biology spring surface, after receptions in 2 hours, in outer layer
Form the layers of nanofibers of fine and close cladding.After it is got on from metal bar, it is placed in 5 in 5% glutaraldehyde/ethyl alcohol & aqueous solution
Minute crosslinks outer gelatin nanofiber, obtains good aqueous stability.It is distilled using 5 ethyl alcohol and 3 times
Water washing removes remaining glutaraldehyde and uncrosslinked gelatin.After freezing 12 hours, it is placed in -20 DEG C, in the freeze drier of 50Pa
Freeze-drying obtains 4 axis 3D printing tubular medical brackets.
2. characterization and detection
The characterization and test of 2.1 morphosis
The characterization of supporting structure is detected by SEM, observes the form of bracket, if it deforms, collapsing and hole
Gap distribution and overall structure.
2.2 Mechanics Performance Testings and characterization
Double layered tubular bracket is cut into 1cm long batten, it is tested and recycles Compressive Mechanical Properties under laid-flat status, is compressed
Shape becomes 50%, speed 20mm/min, and cycle-index 10 times.
2.3 brackets are for internal, outer tubular cartilagines tracheales regeneration
Digestion obtains cartilage cell from New Zealand White Rabbit ear cartilage, and cartilage cell (1.0 × 108cells/ml) is connect
In kind to double layered tubular bracket.Pass through dead cell stain living, Apoptosis test and DNA quantitative analysis after culture 1 day, 4 days
Evaluate the biocompatibility and cells survival situation of bracket.After in vitro culture 8 weeks or in vitro culture 2 weeks replant into nude mice by subcutaneous
After 12 weeks, the test of slice immunohistochemistry and related quantitative analysis, overall merit tubulose regenerating bone or cartilage situation are carried out.
3. result and analysis
The printing of 3.1 Pre-PGS fiber interweaving structures
Experiment has good extrusion performance it is found that PGS prepolymer mixes resulting composite material with salt grain with 1:2, can
It is in linear that continuous uniform, which squeezes out, and wherein salt grain can keep the stability of file printing lines as packing material.Composite wood
Stockline item can be attached to metal bar surface, as print head moves the rotation with metal bar along the direction of metal bar axis,
Material lines structure in the shape of a spiral；Repeatedly reciprocal rear lines are stacked with to form interwoven mesh structure (Fig. 3).This structure can lead to
Print head rate travel and metal bar rotation speed are overregulated to control, the linear speed that the movement speed and metal bar of print head rotate
The ratio between degree is smaller, and spacing is smaller between lines, and intertexture density is bigger, and fenestral porosity is smaller.Also can be used different-diameter or
Receiver of different shapes.
The solidification of 3.2 PGS sleeves and hierarchical porous structure
From the figure 3, it may be seen that Pre-PGS fiber interweaving structure before curing after global shape do not change substantially, this be by
It ensure that the macroscopical tubular structure and microcosmic lines knot for being able to maintain that original printing under the high temperature conditions in the supporting role of salt grain
Structure.It can be seen from PGS sleeve surface electron microscope 4 after hardening, chemical friendship has occurred between the fiber being interweaved
Connection effect, so as to form stable binding site, improves the structural stability of bracket entirety；The diameter of fiber is at 320 μm
Left and right matches with 340 μm of nozzle inside diameter；A large amount of micropore is distributed in fiber surface simultaneously, increases roughness and surface area,
Be conducive to the tactophily of cell.From the section Fig. 5 electron microscope it is found that PGS spring maintains good tubular structure, internal diameter is about
It is that 5mm and used metal bar are substantially uniform-diameter；A large amount of micropore knot is also evenly distributed in the inside of fiber simultaneously
Structure, and these micropores be it is interconnected, provide good mass exchange space for subsequent organizational project application.These above-mentioned points
Cloth derives from stripping of the salt grain as pore-foaming agent in rack surface and internal microcellular structure, and the quantity and size of micropore take
Certainly in salt grain ratio used when preparing composite material and size.
3.3 PGS/ gelatin Double-layer elastic tubular brackets
The gelatine nano fiber formed it can be seen from the pictorial diagram of Fig. 3 and the electron microscope of Fig. 6 by electrostatic spinning is a large amount of
PGS spring surface is deposited and be coated on, one layer of uniform and fine and close layers of nanofibers is formed.The diameter of fiber in nanoscale,
Pattern is good, a smooth no beading.The layers of nanofibers of this densification provides good placeability for bracket, it is ensured that it is having
Body does not leak when applying.In addition nanofiber can preferably simulate natural extracellular matrix because of it on morphosis,
Have the specific surface area of superelevation, therefore good growth microenvironment can be provided for corresponding cell.From the circulation compressing force of Fig. 7
Learn test chart it is found that due to this bioelastomer of internal layer PGS and corresponding sleeve structure double action so that finally
Prepared double layered tubular Medical rack has good elasticity and fatigue durability, it is ensured that energy in dynamic mechanical environment in vivo
Keep good compliance, matching and deformation restorative.
The regeneration of 3.4 tubular trachea cartilages
As can be seen from Figure 8 this Double-layer elastic tubular bracket has good biocompatibility, and cartilage cell is propping up
There is preferable existing state and apparent proliferation on frame.It can be seen in figure 9 that after in vitro culture 8 weeks, using bracket as template
Grow apparent tubulose cartilage structure.After HE, Safranin-O, masson and type II collagen dyeing, it can see
Apparent cartilage structure out.Equally, it can be seen from fig. 10 that being implanted into nude mice by subcutaneous after two weeks by Cell culture invitro into one
Step culture can prove to obtain mature tubulose cartilage by dyeing.Be implanted directly into using tubular bracket it is subcutaneous as negative control group,
Normal cartilage always contains the weight of sample, thickness, Young's modulus, DNA content, glycosaminoglycan content, collagen as positive control group
Amount carries out test and quantitative analysis.It may indicate that double layered tubular bracket can regenerate the cartilage of tubulose maturation, and in items
There are preferable performance and result in feature.
4. conclusion
The present embodiment provides a kind of preparation methods of 4 axis 3D printing tubular medical brackets, and this method solve extruded type 3D
Printing is difficult to prepare thin-walled porous tubular scaffolds root problem, and prepared Medical rack has double-layer structure, and internal layer is fibre
The spring structure of intertexture shape is tieed up, outer layer is the layers of nanofibers of even compact cladding.With the multistage of controllable precise in structure
Pore structure, there is excellent elasticity and a suture property in mechanical property, method is simple, it is quick, be suitable for a variety of biomaterials,
Application example is used as using cartilagines tracheales regeneration, it was demonstrated that the tubular bracket can regenerate the tubulose cartilage structure of maturation, have
Good application prospect.
Embodiment 2
1. preparation process
Polycaprolactone (PCL) tubular bracket of 1.1 3D printing difference macroscopic forms
The PCL of 80000 molecular weight is preheated 30 minutes for 200 DEG C in printer, melts it sufficiently, is led under the conditions of 180 DEG C
It crosses 22G syringe needle and is extruded into uniform fiber, and be deposited on rotatably receiving device.The shape of control receiving device can obtain
Obtain the tubular bracket of different shape structure.Wherein the internal diameter of printer heating compartment is (De)18mm。
The PCL tubular bracket of 1.2 3D printing diverse microcosmic structures
Under above-mentioned print conditions, diameter (D is usedr) 5.14cm cylindric receiving device, keep rate of extrusion (Ve)
For 0.03mm/min, nozzle rate travel is (Vm) 1mm/s, round-trip printing 5 times.Control and receive the speed of rotation n difference of device
It is 10,20,30,40min/r.
1.3 3D printing extravascular cuffs brackets
PCL is blended with rapamycin drug as printing raw material.Using the rotation receiving device of 1.5mm outer diameter, printing
It is 1.5mm in out, the tubulose that outer diameter is 2mm carries medicine tubular bracket, and the extravascular cuffs as rat aorta use.
1.4 operation method
Using male SD rat (250-300g), amobarbital (30mg/kg) intraperitoneal injection of anesthesia, dorsal position is conventional standby
Skin, disinfection, drape.Right side nutator fore edge is taken, 3cm is about, successively cuts skin, subcutaneous tissue, blunt separation jaw
Lower gland, is turned over, and vena jugularis externa, length about 1.5cm are appeared and separate.Take Vein Bridge length about 1.5cm, two broken ends of fractured bone 8-0
Atraumatic suture ligation rinses lumen with heparin-saline (containing heparin 12500U/L), until tube wall whitens, without attached wall blood
Bolt is placed in wherein to save and continue to employ.Vascular cuffing (length about 5mm) is prepared with venous detaining needle, away from quarter at end about 1mm
Groove is drawn with fixation to be ligatured.Muscle bundle is retracted between ipsilateral nutator and sternohyoideus, appears carotid sheath, is dissociated
Arteria carotis communis about 2cm.Arteria carotis communis both ends heparin is used with not damaged blood vessel clip blocking blood flow, 0.3~0.5cm of centre excision
Salt water rinses lumen.In blood vessel two sides, the broken ends of fractured bone respectively stitches 2 8-0 draught lines, first guides proximal part artery and wears out of self-control vascular cuffing
It crosses, gently pulls draught line, under Smooth forceps auxiliary, the turned-out pivoted housing of artery is fixed into blood vessel outside vascular cuffing, and be inserted into
The vein distal end (purpose of reversing is the blood supply for preventing from having tiny veins valve to influence after transplanting in vein blood vessel) of reversing, with 8-
0 nylon wire is ligatured in groove.It guides vein to pass through External stent, then in kind fixes distal end artery and proximal part
Vein after determining that vein graft blood vessel is determined by secured ligation set, slowly unclamps noninvasive blood folder and restores vessel bridges blood flow, Vein Bridge
Color reddens, and illustrates that blood flow is unobstructed, it is obvious to fill and has beating hints model to be successful.
2. characterization and detection
The characterization and test of 2.1 morphosis
The characterization of supporting structure is detected by SEM, observes the form of bracket, if deforms, collapses.To difference
The bracket of microstructure measures dependency structure parameter, including spiral interval S, fiber spacing L, fibre diameter Df, fiber friendship
Knit 2 θ of angle.Print procedure is modeled simultaneously, theoretical formula is constructed to corresponding construction parameter according to model.
2.2 ultrasound detection
1 after vein transplantation, 4,8W row Sonography, measurement bridge blood vessel diameter, blood flow direction and judge unobstructed be in
Degree.
2.3 morphological analysis
The postoperative 8W of vein transplantation anaesthesia experiment animal again, former notch exposure dividing vein bridge, together with both ends arterial portions
It cuts together, PBS rinses blood clot after materials, fixed rear for 24 hours spare as 4% paraformaldehyde.HE, Masson dyeing, observation
Tissue morphology measures intravascular, outer diameter, endangium, media thickness.
2.4 immunohistochemistry: PCNA, TGF-b1, Vimentin, α-SMA observe blood vessel lining cells hyperplasia degree.TUNEL
Observe Apoptosis situation.
3. result and analysis
The control of the form and microstructure of 3.1 PCL control brackets
The macroscopic form of tubular bracket and rotating device matching are good it can be seen from Figure 11 a-i.By this method
The tubular bracket of different-diameter can easily be obtained.Using the reception device of anisotropic approach, it is uniform pattern can be quickly obtained
Various anisotropic tubular brackets, interface includes triangle, hexagon etc..It can be seen that the reason of bracket printing by Figure 12 a-g
By model and forming process, the fiber of extrusion is interlaced with one another to form reticular structure.With the increase of revolving speed, the braiding of fiber mesh
Density increases.It is as follows according to the theoretical parameter for calculating corresponding construction according to model:
By Figure 13 a-d it is found that spiral spacing (S), fiber spacing (L), fibre diameter (Df) and 2 θ of fiber interweaving angle with
The revolving speed (n) of reception device is inversely proportional, and the structural parameters and theoretical curve height of experiment sample are fitted, and has good controllability
And reproducibility.
3.2 PCL tubular brackets are used for thin vessels housing
As shown in Figure 14, the extravascular cuffs bracket that PCL tubular bracket can be used for after vein transplantation.Bracket has good soft
Property, show the matching with blood vessel.As shown in Figure 15, support arm can prevent limitation phlebectasia, maintain vein graft and
The internal diameter consistency of target vessel stablizes haemodynamics, reduces turbulent flow, antithrombotic.Not only may be used using External stent
With antithrombotic, and vein graft endometrial hyperplasia can be reduced, improve long-term patency rate.
4. conclusion
The present embodiment provides a kind of preparation method of 4 axis 3D printing tubular medical brackets, which can load a variety of anti-
The drug of solidifying, antiplatelet and anti-endometrial hyperplasia.Bracket can regulate and control its macroscopic form and microstructure, and it is personalized fixed to show
The advantage of system.As support arm, mechanics mismatch is brought after stable reticular structure can effectively prevent vein transplantation
Blood vessel dilatation, the combined treatment of carrying medicament can prevent endometrial hyperplasia, stablize blood flow, maintain unimpeded rate at a specified future date.
Claims (10)
1. a kind of 4 axis 3D printing tubular medical brackets, it is characterised in that: the sleeve including nanofiber and 4 axis 3D printings
Bracket, nano fiber coated form double-layer structure in rack surface；Multistage pore structure includes linear in sleeve bracket
Hole that material interweaves, the micropore or nano-pore and nanofibres deposit for being uniformly distributed and being interconnected in wire member,
The nanoaperture structure for wrapping, being interweaved and being formed.
2. a kind of preparation method of 4 axis 3D printing tubular medical brackets, comprising:
(1) gel like material, thermoplastic material or thermosetting material and packing material 1:0.5-3 in mass ratio are mixed to get
Composite material as ink material, being squeezed out ink material by 3D printing is in linear；It is flat using rotating device as receiving
Platform, the two cooperate to form the 4 axis formation systems of X/Y/Z/Rotation, obtain the tubular bracket with spring structure；
(2) tubular bracket with spring structure is subjected to solidification crosslinking, then remove packing material to get with micropore or
The sleeve bracket of nano-pore structure；
(3) the sleeve branch that step (2) obtains is placed on rotating device or there is spring knot by what step (1) obtained
The tubular bracket of structure is placed directly on rotating device without step (2), is received as receiving platform and is passed through electrostatic spinning institute shape
At nanofiber, make nano fiber coated in rack surface to get 4 axis 3D printing tubular medical brackets.
3. a kind of preparation method of 4 axis 3D printing tubular medical bracket according to claim 2, it is characterised in that: described
Gel like material in step (1) is polyacrylamide, sodium alginate, collagen, gelatin or fibroin；Thermoplastic material is to gather oneself
Lactone, polylactic acid, poly lactide-glycolide acid or thermoplastic polyurethane；Thermosetting material be poly- decanedioic acid glyceride,
Heat-curable urethane or epoxy resin.
4. a kind of preparation method of 4 axis 3D printing tubular medical bracket according to claim 2, it is characterised in that: described
Packing material in step (1) be salt particle, graphene, carbon nanotube, bio-vitric, silica, inorganic ceramic class material,
Nano clay, nano short fiber, biotic factor or drug.
5. a kind of preparation method of 4 axis 3D printing tubular medical bracket according to claim 2, it is characterised in that: described
Hybrid mode in step (1) is solvent mixing method or heating.
6. a kind of preparation method of 4 axis 3D printing tubular medical bracket according to claim 2, it is characterised in that: described
The technological parameter of 3D printing in step (1) are as follows: extrusion chamber temperature is 0~250 DEG C with nozzle temperature, and XY axis movement velocity is arranged
For 0.1~20mm/s, T axis material extrusion speed is 0.008-0.1mm/s, reception device 5~150r/min of rotation speed, and receiver is straight
Diameter is 2~20mm, and receiver cross sectional shape is round, oval, triangle or quadrangle.
7. a kind of preparation method of 4 axis 3D printing tubular medical bracket according to claim 2, it is characterised in that: described
Solidification crosslinking in step (2) is heat cross-linking, photo-crosslinking or other modes crosslinking.
8. a kind of preparation method of 4 axis 3D printing tubular medical bracket according to claim 2, it is characterised in that: described
The pore-size distribution of sleeve bracket in step (2) is 10 nanometers to 100 microns.
9. a kind of application of 4 axis 3D printing tubular medical bracket as described in claim 1, it is characterised in that: can directly or
Person combines antiplatelet or anticoagulant, the External stent as coronary bypass medium sized vein graft.
10. a kind of application of 4 axis 3D printing tubular medical bracket as described in claim 1, it is characterised in that: in conjunction with Related Drug
Object or active factors are used as tracheae regeneration biological bracket.
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