CN107496060A - A kind of three-dimensional artificial total spinal disc and its preparation method and application - Google Patents
A kind of three-dimensional artificial total spinal disc and its preparation method and application Download PDFInfo
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
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- A61F2/44—Joints for the spine, e.g. vertebrae, spinal discs
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- A—HUMAN NECESSITIES
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- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/3094—Designing or manufacturing processes
- A61F2/30942—Designing or manufacturing processes for designing or making customized prostheses, e.g. using templates, CT or NMR scans, finite-element analysis or CAD-CAM techniques
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A61F2/30—Joints
- A61F2/44—Joints for the spine, e.g. vertebrae, spinal discs
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- A61L2430/38—Materials or treatment for tissue regeneration for reconstruction of the spine, vertebrae or intervertebral discs
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Abstract
The invention provides a kind of three-dimensional artificial total spinal disc, and its preparation method and application.The spinning film that the present invention is prepared for having highly hydrophilic, water-retaining property and biocompatibility by blending PLGA, PCL and collagen.The three-dimensional artificial total spinal disc of the present invention can be with the micro-nano structure in analogue body, show good biocompatibility simultaneously, the orderly nanofiber in cell experiment surface can align growth with inducing cell, it can be effectively combined after the implantation of zoopery surface artificial interverbebral disc with surrounding tissue together, forming one can be with the mechanics active unit of free movement.
Description
Technical field
The invention belongs to biomedical sector, and in particular to a kind of three-dimensional artificial total spinal disc, and preparation method thereof and should
With.
Background technology
Chronic neck and flank pain are the high illnesss of the incidence of disease, and annual a huge sum of money all spends in intervertebral disc disorder and drawn
In the treatment for sending out disease.Different degrees of neck and back pain are suffering from according to the individual of more than 50 years old of the statistics more than 97%
Bitterly.Most common waist and cervical pain and the lesion in interverbebral disc are closely related, are mainly caused by vertebral disc portion lesion.Mesh
The preceding treatment to degenerative disc disease arrives operative treatment (diskectomy, ridge including expectant treatment (medicine and physiotherapy)
Post merges and intervertebral disc replacement), but these treatments can be with pain of alleviation or recovery disc material function, can not be fundamentally
Cure.Human body shares 23 interverbebral discs (intervertebral disc)：Interverbebral disc is rich by upper and lower ends cartilage endplate, periphery
Three parts of the nucleus pulposus of fibrous ring and center rich in proteoglycan containing collagen form.
Fibrous ring has multilayer concentric cyclic structure, has bonding sample material letter each other is firmly bonded to one between each layer
Rise, be connected in innermost layer fiber and entrance nucleus pulposus and with cytoplasm.Whole fibrous ring is in almost concentric arrays, in each ring
Portion's fiber is arranged in parallel in 30~45 ° along same cross section, and the arrangement of adjacent ring is opposite.Fibrous ring is very firm, close attached
On cartilage endplate, keep the stability of backbone.Nucleus pulposus is the translucent colloid of milky, springiness, is interverbebral disc knot
A part for structure, between two cartilage plates and fibrous ring, the elastic gel thing that is made up of cartilage cell and proteoglycan matrix
Matter.
With the development of organizational project regenerative medicine in recent years, go to create by using the theoretical method of biology and engineering science
The tissue and organ of loss or functional lesion are made, makes that it possesses the mechanism of normal structure and organ and function to rebuild tissue work
This target of the artificial intervertebral disk of journey is intended to possibility.There are large quantities of science researchers to be engaged in both at home and abroad engineered
The research of artificial intervertebral disk, engineered artificial intervertebral disk are concentrated mainly on engineered Single Fiber ring or single marrow
Core.It is always the focus of Tissue Engineering Study wherein due to the unique anisotropic structure of fibrous ring.Currently used for building tissue
The timbering material of technical fiber ring mainly includes natural biologic material, synthetic material and composite three major types.Naturally
Biomaterial has decellularization fibrous ring, collagen, Silk fibroin gel etc.；Synthetic material has and had including synthetic material
Polyamide, polycaprolactone etc., composite such as PLA/hyaluronic acid, elastin laminin/glycosaminoglycan/collagen etc..Artificial nucleus
Mainly with natural material such as marine alga gel, collagen type II gel, aggrecanase and hyaluronic acid isogel material.Mesh
The artificial intervertebral disk of preceding report still can not well in analogue body interverbebral disc three-dimensional structure, and formed feature implantation replace
For thing.Main facing challenges are as follows during bionical disc tissue is developed：(1) fibrous ring is anisotropic in analogue body
All in the same direction+30 ° or -30 ° of collagenous fibres are oriented parallel in each ring of fibrous ring of multilevel hierarchy, i.e. concentric annular
Arrangement, the nanofiber orientation cut in adjacent two layers ring are opposite；(2) structure is made up of annulus fibrosus portion and nucleus pulposus portion
Feature total spinal disc.
Electrostatic spinning is to obtain to develop rapidly and most have a kind of nano/micron superfine fibre of application potential to prepare skill in recent years
Art one, prepared fibre diameter are generally commonly called as nanofiber in submicron order, can be preferable to realizing in size and pattern
It is bionical, preferably existence microenvironment is provided for cell, thus there is more preferable cell and histocompatbility.Because electrostatic spinning is penetrated
The uncontrollability of stream, the non-woven fabrics form that nano fiber scaffold prepared by conventional method is mostly arbitrarily arranged in machine direction, this
Fine for building anisotropy that is higher to mechanical property requirements and needing fiber to be formed in Orienting ordered arrangement each time
Dimension ring is still the problem of a great challenge.
The content of the invention
Therefore, it is an object of the invention to overcome in the prior art the defects of, there is provided a kind of three-dimensional artificial total spinal disc, and
Its preparation method and application.
Before present invention is illustrated, it is as follows to define term used herein：
Term " PCL " refers to：Polycaprolactone.
Term " PLGA " refers to：Poly- D, L- lactide-co-glycolide [poly (lactic-co-glycolic acid)].
Term " Collagen " refers to：Collagen.
Term " HFIP " refers to：Hexafluoroisopropanol.
Term " IVD " refers to：Interverbebral disc (intervertebral disc).
Term " AF " refers to：Fibrous ring (annulus fibrosus).
Term " NP " refers to：Nucleus pulposus (nucleus pulposus).
To achieve the above object, the first aspect of the present invention provides a kind of three-dimensional artificial total spinal disc, and the interverbebral disc includes：
The anisotropic artificial fiber ring built using orderly spinning；With
Artificial nucleus.
Interverbebral disc according to a first aspect of the present invention, wherein, orderly spinning described in the artificial fiber ring forms angle
Respectively 0 °~90 ° scopes, most preferably+30 ° and -30 ° of the long band of strip spinning crimp around axle forms cyclic structure, ring
Fiber is into aligning in interior same layer, and the fiber direction in adjacent two layers is opposite.
Interverbebral disc according to a first aspect of the present invention, wherein, the material of the artificial fiber ring is selected from following one kind or more
Kind：PCL, PLGA and collagen；
Preferably, the material of the artificial fiber ring is the mixture of PCL, PLGA and collagen；
It is highly preferred that the quality proportioning of PCL, PLGA and collagen is 2~4 in the mixture:2~3:1, further
Preferably 4:2:1、2:2:1、3:3:1 or 4:3:1, most preferably 3:3:1.
Interverbebral disc according to a first aspect of the present invention, wherein, the artificial nucleus passes through based on sodium alginate and calcium sulfate
The marine alga gel structure of preparation.
The second aspect of the present invention provides the preparation method described in first aspect, and the preparation method can include following
Step：
(1) by PLGA, PCL and collagen be dissolved in hexafluoroisopropanol prepare spinning before liquid；
(2) electrostatic spinning is carried out to liquid before the spinning described in step (1), and is prepared using the roller collection device rotated
Orderly spinning；
(3) the orderly spinning obtained in step (2) is cut to strip, makes the major axis of spinning orientation and strip in length
Bar, then two layers of spinning membrane stack is gathered into folds, then rolls to form multilayer concentric circular ring structure around circular shaft, per adjacent two layers
Spinning is arranged in order respectively, and the artificial fiber ring is made；
(4) CaSO is mixed4Solution and sodium alginate soln, mixed solution is poured into nucleus pulposus template, cylindric nucleus pulposus is made
Gel；
(5) by the obtained artificial fiber ring in the obtained nucleus pulposus gel Embedded step (3) in step (4),
The interverbebral disc is made.
Preparation method according to a second aspect of the present invention, wherein, in the step (1), the concentration of liquid is before the spinning
10%w/v；And/or
Described PCL, PLGA and collagen mass ratio are 2~4:2~3:1；Preferably, described PCL, PLGA and collagen
The mass ratio of albumen is 3:3:1.
In the step (2), the electrostatic spinning process adds voltage 15kV, 1mL h using 17G syringe needles-1Enter liquid speed
Degree carries out spinning；And/or
The linear velocity of the roller is 13ms-1。
In the step (4), the CaSO4The concentration of solution is 0~0.1g/mL, and excellent is 0.01~0.03g/mL, optimal
Elect 0.02g/mL as；
The sodium alginate soln concentration is 1%~20%w/v, preferably 2%w/v~5%w/v, most preferably 3%w/v；
CaSO in the mixed solution4The volume ratio of solution and sodium alginate soln is 1:10~10:1, preferably 1:2~
2:1, most preferably 1:1.
The third aspect of the present invention provide it is described in first aspect or according to described in second aspect method prepare three
Tie up application of the prosthetic total disc in tissue engineering material.
Preferably, the tissue engineering material is the material for triggering disease for intervertebral disc disorder.
This research is from PCL, PLGA and the internal born of the same parents that three kinds of biodegradable polymer materials are by FDA approval of certification
Epimatrix ultimate constituent Collagen prepares the nanometer spinning with higher order structures, passed through as research object
Cut into+30 ° and -30 ° of the long band of strip spinning and crimp composition cyclic structure around axle, arranged in ring with fiber in layer into orientation
Row, and fiber direction in adjacent two layers on the contrary, so as in success analogue body fibrous ring it is each to heterogeneousization structure.Pass through
The spinning film of high-sequential is prepared, and to simulate fibrous ring three-dimensional multistage knot in structure analogue body by the method crimped along circular shaft
Structure.Build the fibrous ring based on spinning and the artificial intervertebral disk based on marine alga acid gel nucleus pulposus structure.
Find that PLGA belongs to semicrystalline copolymers in experimental study, so pure PLGA spinning can occur in the solution
75% shrinks, it is impossible to meet our requirement of experiment, and pure PCL it is soaked after swelling action can occur, when we are PLGA and PCL
Spinning obtained by after mixing can effectively avoid shrinking and Swelling.On the other hand, because PLGA and PCL are height
Hydrophobic, and interverbebral disc is a kind of very high gel component of moisture, so we add Collagen to improve spinning
Hydrophily, and collagen is the main component in human intervertebral disc, the extracellular matrix added in the more preferable analogue body of collagen
Structure and composition, be advantageous to the regeneration of fibrous ring.
The invention provides a kind of method for preparing complete artificial intervertebral disk, using orderly PCL PLGA
Collagen spinning come build anisotropic fibrous ring and based on sodium alginate calcium sulfate prepare marine alga gel construct people
Work nucleus pulposus, then using rat as animal model by full artificial disc replacement rat tail bone interverbebral disc, experimental group tail bone by
In disc removal in basic fusion after two months, and the rat tailses of experimental group implantable artificial interverbebral disc are newly born similar to vertebra
The soft tissue of the high-moisture of disk, and rat tail being capable of free movement, it was demonstrated that and this artificial intervertebral disk rises to a certain extent
Repair the effect of rat disc.
By PLGA [poly (lactic-co-glycolic acid), PLGA, 50/50], gather
Caprolactone (polycaprolactone, PCL, Mn=80000), collagen prepare PPC-I (PCL according to different ratio respectively：
PLGA：Collagen=4：2：1), PPC-II (PCL：PLGA：Collagen=2：2：1), PPC-III (PCL：PLGA：
Collagen=3：3：1), PPC-IV (PCL：PLGA：Collagen=4：3：1), it is molten to be dissolved in HFIP for pure PLGA and pure PCL preparations
Liquid is configured to 10%w/v solution.Stirred on magnetic stirring apparatus 24 hours until its uniform dissolution.We are quiet using customization
Voltage of the electrospinning device in 15kV and the 1mLh by 17G stainless pins-1Feed rate under electrostatic spinning prepare PCL/
PLGA/ collagen nanofibers.For unordered spinning, we use static flat panel collector device, by the way that ES fibers are deposited to
Unordered ES films are prepared on static collection device.For orderly electrostatic spinning, we are rolled using the rotation that linear velocity is 13m/s
Cylinder collection device collects orderly ES films.
It will be cut into strips according to the orderly spinning that above-mentioned steps obtain afterwards, make spinning orientation and strip
Major axis is in +/- 30 ° of strip, and then+30 ° and -30 ° of two layers of spinning membrane stacks gather into folds, then roll to be formed around circular shaft
Multilayer concentric circular ring structure, the spinning per adjacent two layers are arranged in order into+30 ° and -30 ° respectively.
0.02g/mL CaSO are prepared respectively4With 3% (wt/vol) sodium alginate soln, nucleus pulposus template is poured into after both are mixed,
It is prepared into cylindric nucleus pulposus gel.Nucleus pulposus gel is embedded in fibrous ring well prepared in advance, prepares a complete interverbebral disc.
This problem mainly studies the nucleus pulposus based on the anisotropic fibrous ring of PPC-III spinning and based on sodium alginate gel
The function and histocompatbility of the artificial intervertebral disk implantation prosthese of composition.First, this problem structure has orientation on a microscopic scale
PPC-III nanometer spinning arranged in parallel, AFCs cells are induced to determine by orderly electrostatic spinning (Electrospining, ES)
To arrangement；Afterwards, on a macroscopic scale, fiber ring structure prepares the artificial fiber ring with identical multilevel hierarchy in analogue body；Most
Afterwards by building the total spinal disc with bionic fiber ring and nucleus pulposus, and carry out experiment in vivo and evaluate its function and histocompatbility.
The three-dimensional artificial total spinal disc of the present invention can have but be not limited to following beneficial effect：
1. the present invention is prepared for having highly hydrophilic, water-retaining property and biofacies by blending PLGA, PCL and collagen
The spinning film of capacitive.
2. the three-dimensional artificial total spinal disc of the present invention can be with the micro-nano structure in analogue body, while shows good biofacies
Capacitive, the orderly nanofiber in cell experiment surface can align growth, zoopery surface artificial intervertebral with inducing cell
It can be effectively combined after disk implantation with surrounding tissue together, forming one can be with the mechanics active unit of free movement.
Brief description of the drawings
Hereinafter, embodiment of the present invention is described in detail with reference to accompanying drawing, wherein：
Fig. 1 shows preparation and the implantation flow chart of artificial intervertebral disk.
Fig. 2 shows the water contact angle test result of the spinning film of different proportion blending.
Fig. 3 shows the infrared spectrogram of the spinning film of different mixing proportion.
Fig. 4 shows the measuring mechanical property result of different spinning films.
Fig. 5 shows that degradation time is observed in the spinning environmental microbes of 0,2,4 week respectively.
Fig. 6 difference spinning films measure (A) water absorption rate, (B) mass loss and (C) nanometer spinning in 0,1,2,3,4 week in degraded
The change of fibre diameter.
Fig. 7 shows (A), and the SEM of PPC-III spinning and (B) unordered PPC-III spinning schemes in order.
Fig. 8 shows AFCs cellular morphology observations on orderly (a, c) and unordered (b, d) PPC-III spinning.Cytoskeleton
Dyed respectively with TM 488phalloidin (green) and Hoechst 33342 (blueness) with nucleus.Scheming (A, B) is
Observed with 20 ×/0.8NA object lens, figure (C, D) is observed with 63 ×/1.4NA oil mirrors.
Fig. 9 show culture in orderly and unordered PPC-III spinning AFCs nucleus degrees of order statistical result (A) and carefully
Born of the same parents' shape index (B).
Figure 10 shows that the interface laser confocal microscope for the artificial fiber ring that (a) is prepared based on PPC-III spinning is seen
Figure is examined, adjacent two layers are dyed with DiO (green) and DiD (red) dyestuff respectively.(b) nucleus pulposus cell is on marine alga gel
Dead coloration result living.
Figure 11 is fixed after showing rat tailses interverbebral disc implant surgery by fixing device.
Figure 12 shows interverbebral disc based on PPC-III, PLGA and discectomy group after surgery behind 0 day, 1 and 3 months
NMR imaging result.
Figure 13 shows histopathological analysis.(A) normal IVD, (B) PPC-III IVD, (C) PLGA IVD and (D) intervertebral
Rat tail bone internal anatomy of HE dyeing observation (E) the artificial intervertebral disk implantation group and excision group in disk excision group postoperative March after 3 months.
Embodiment
The present invention is further illustrated below by specific embodiment, it should be understood, however, that, these embodiments are only
It is used for specifically describing in more detail, and is not to be construed as limiting the present invention in any form.
This part carries out general description to the material and test method that are arrived used in present invention experiment.Although it is
Realize that many materials used in the object of the invention and operating method are it is known in the art that still the present invention still uses up herein
It may be described in detail.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour
It is well known in the art as method.
The reagent and instrument used in following examples is as follows：
Reagent name
Laboratory apparatus
Embodiment 1
The present embodiment is used for the preparation method for illustrating PPC-I interverbebral discs of the present invention.
According to PCL：PLGA：Collagen is 4：2：1 mass ratio 1g is dissolved in 10mL hexafluoroisopropanols and prepares 10% spinning
Liquid before silk, then prepares orderly and unordered PPC-I spinning according to the method spinning of embodiment 1.Voltage is added in 17G syringe needles
15kV, 1mL h-1 feed speed carry out spinning.We prepare unordered spinning using static collection device, utilize line
Speed is in 13m s-1The roller collection device of high-speed rotation prepares orderly spinning.Have afterwards by what is obtained according to above-mentioned steps
Sequence spinning, which is cut, into strips, makes the major axis of spinning orientation and strip be in +/- 30 ° of strip, then will+30 ° and-
30 ° of two layers of spinning membrane stacks gather into folds, and then roll to form multilayer concentric circular ring structure around circular shaft, the spinning per adjacent two layers point
It is not arranged in order into+30 ° and -30 °, prepares fibrous ring.
0.02g/mL CaSO are prepared respectively4With 3% (wt/vol) sodium alginate soln, 1/1 both are mixed by volume
After pour into nucleus pulposus template, be prepared into cylindric nucleus pulposus gel.Nucleus pulposus gel is embedded in fibrous ring well prepared in advance, prepared
One complete interverbebral disc.
Embodiment 2
The present embodiment is used for the preparation method for illustrating PPC-II interverbebral discs of the present invention.
According to PCL：PLGA：Collagen is 2：2：1 mass ratio 1g is dissolved in 10mL hexafluoroisopropanols and prepares 10% spinning
Liquid before silk, then prepares orderly and unordered PPC-II spinning according to the method spinning of embodiment 1.Voltage is added in 17G syringe needles
15kV, 1mL h-1Feed speed carry out spinning.We prepare unordered spinning using static collection device, utilize linear speed
Degree is in 13m s-1The roller collection device of high-speed rotation prepares orderly spinning.It will be obtained afterwards according to above-mentioned steps orderly
Spinning, which is cut, into strips, makes the major axis of spinning orientation and strip be in +/- 30 ° of strip, then will+30 ° and-
30 ° of two layers of spinning membrane stacks gather into folds, and then roll to form multilayer concentric circular ring structure around circular shaft, the spinning per adjacent two layers point
It is not arranged in order into+30 ° and -30 °, prepares fibrous ring.
0.02g/mL CaSO are prepared respectively4With 3% (wt/vol) sodium alginate soln, 1/1 both are mixed by volume
After pour into nucleus pulposus template, be prepared into cylindric nucleus pulposus gel.Nucleus pulposus gel is embedded in fibrous ring well prepared in advance, prepared
One complete interverbebral disc.
Embodiment 3
The present embodiment is used for the preparation method for illustrating PPC-III interverbebral discs of the present invention.
According to PCL：PLGA：Collagen is 3：3：1 mass ratio 1g is dissolved in 10mL hexafluoroisopropanols and prepares 10% spinning
Liquid before silk, then prepares orderly and unordered PPC-III spinning according to the method spinning of embodiment 1.Voltage is added in 17G syringe needles
15kV, 1mL h-1Feed speed carry out spinning.We prepare unordered spinning using static collection device, utilize linear speed
Degree is in 13m s-1The roller collection device of high-speed rotation prepares orderly spinning.It will be obtained afterwards according to above-mentioned steps orderly
Spinning, which is cut, into strips, makes the major axis of spinning orientation and strip be in +/- 30 ° of strip, then will+30 ° and-
30 ° of two layers of spinning membrane stacks gather into folds, and then roll to form multilayer concentric circular ring structure around circular shaft, the spinning per adjacent two layers point
It is not arranged in order into+30 ° and -30 °, prepares fibrous ring.
0.02g/mL CaSO are prepared respectively4With 3% (wt/vol) sodium alginate soln, 1/1 both are mixed by volume
After pour into nucleus pulposus template, be prepared into cylindric nucleus pulposus gel.Nucleus pulposus gel is embedded in fibrous ring well prepared in advance, prepared
One complete interverbebral disc.
Embodiment 4
The present embodiment is used for the preparation method for illustrating PPC-IV interverbebral discs of the present invention.
According to PCL：PLGA：Collagen is 4：3：1 mass ratio 1g is dissolved in 10mL hexafluoroisopropanols and prepares 10% spinning
Liquid before silk, then prepares orderly and unordered PPC-IV spinning according to the method spinning of embodiment 1.Voltage is added in 17G syringe needles
15kV, 1mL h-1Feed speed carry out spinning.We prepare unordered spinning using static collection device, utilize linear speed
Degree is in 13m s-1The roller collection device of high-speed rotation prepares orderly spinning.It will be obtained afterwards according to above-mentioned steps orderly
Spinning, which is cut, into strips, makes the major axis of spinning orientation and strip be in +/- 30 ° of strip, then will+30 ° and-
30 ° of two layers of spinning membrane stacks gather into folds, and then roll to form multilayer concentric circular ring structure around circular shaft, the spinning per adjacent two layers point
It is not arranged in order into+30 ° and -30 °, prepares fibrous ring.
0.02g/mL CaSO are prepared respectively4With 3% (wt/vol) sodium alginate soln, 1/1 both are mixed by volume
After pour into nucleus pulposus template, be prepared into cylindric nucleus pulposus gel.Nucleus pulposus gel is embedded in fibrous ring well prepared in advance, prepared
One complete interverbebral disc.
Embodiment 5
The present embodiment is used for the preparation method for illustrating PCL interverbebral discs of the present invention.
Pure PCL1g is dissolved in 10mL hexafluoroisopropanols and prepares liquid before 10% spinning, then according to the method spinning of embodiment 1
Prepare orderly and unordered PCL spinning.Voltage 15kV, 1mL h are added in 17G syringe needles-1Feed speed carry out spinning.We
Unordered spinning is prepared using static collection device, using linear velocity in 13m s-1The roller collection device of high-speed rotation comes
Prepare orderly spinning.It will be cut into strips according to the orderly spinning that above-mentioned steps obtain afterwards, make spinning orientation
Major axis with strip is in +/- 30 ° of strip, and then+30 ° and -30 ° of two layers of spinning membrane stacks gather into folds, and is then rolled up around circular shaft
Get up to be formed multilayer concentric circular ring structure, the spinning per adjacent two layers is arranged in order into+30 ° and -30 ° respectively, prepares fiber
Ring.
0.02g/mL CaSO are prepared respectively4With 3% (wt/vol) sodium alginate soln, 1/1 both are mixed by volume
After pour into nucleus pulposus template, be prepared into cylindric nucleus pulposus gel.Nucleus pulposus gel is embedded in fibrous ring well prepared in advance, prepared
One complete interverbebral disc.
Embodiment 6
The present embodiment is used for the preparation method for illustrating PLGA interverbebral discs of the present invention.
Pure PLGA 1g are dissolved in 10mL hexafluoroisopropanols and prepare liquid before 10% spinning, then spinning according to the method described above
Prepare orderly and unordered PLGA spinning.Voltage 15kV, 1mL h are added in 17G syringe needles-1Feed speed carry out spinning.I
Unordered spinning is prepared using static collection device, using linear velocity in 13m s-1The roller collection device of high-speed rotation
To prepare orderly spinning.It will be cut into strips according to the orderly spinning that above-mentioned steps obtain afterwards, make spinning arrangement side
It is in +/- 30 ° of strip to the major axis with strip, then+30 ° and -30 ° of two layers of spinning membrane stacks gathers into folds, then around circular shaft
Roll to form multilayer concentric circular ring structure, the spinning per adjacent two layers is arranged in order into+30 ° and -30 ° respectively, prepares fiber
Tie up ring.
0.02g/mL CaSO are prepared respectively4With 3% (wt/vol) sodium alginate soln, 1/1 both are mixed by volume
After pour into nucleus pulposus template, be prepared into cylindric nucleus pulposus gel.Nucleus pulposus gel is embedded in fibrous ring well prepared in advance, prepared
One complete interverbebral disc.
Test example 1
This test example carries out in-vitro evaluation based on artificial intervertebral disk prepared by embodiment 1~6.
The vitro characterization of spinning film, specific experiment method include：
(1) tensile strength test：We measure the tensile strength of spinning membrane material with universal machine analyzer.Sheet material is cut into
Dumbbell specimens, and the distance between two fixtures are arranged to 50mm.We are under 25 DEG C, 50% relative humidity with 10mm/
Min draw speed test all samples.As a result it is as shown in Figure 4.
(2) Fourier transform infrared spectroscopy (FTIR) is analyzed：We are studied by ftir analysis and spun
The structure of cortina.We are collected 500 to 4000cm-1In the range of spectrum, resolution ratio 0.5cm-1.As a result it is as shown in Figure 3.
(3) hydrophilicity analysis：We assess the hydrophily of spinning membrane material with water contact angle analysis system.We are by 3L volumes
Water droplet drop in respectively on the surface of spinning film, the contact angle of measurement spinning film surface water droplet.Every group is made up of five samples.Knot
Fruit is as shown in Figure 2.
(4) degraded test：Spinning film is immersed at 37 DEG C in phosphate buffer solution (phosphatic by we
Buffer solution, PBS) degradation experiment is carried out, sample is taken out from PBS solution at 0,1,2,3 and 4 week be used in combination respectively
Ultra-pure water immersion removes PBS salt solutes, measures the quality (W under hygrometric state respectivelywet) and vacuum freeze drying after dry state under matter
Measure (Wdry) and its morphological change is characterized by SEM.And the surface shape of each spinning in each degraded period is observed with SEM
Looks, with the analysis fibre diameter of the SEM image of Image J software analysis 5000X multiplication factors, every group of sample size at least five
It is individual.As a result it is as shown in Figure 5.
(5) water absorbing capacity is tested：We analyze the water absorbing capacity of sheet material by testing the weight increase of wet-sheet, and lead to
Degradation property is analyzed in the mass loss for crossing spinning film after measurement degraded.We calculate water absorption rate (W according to below equationu, %)
With weight loss (WL, %)：
Wu(%)=(Wwet-W0)/W0×100 (1)
WL(%)=(Wdry-W0)/W0×100 (2)
In equation (1) and (2), W0It is the initial weight of dry ES samples, WwetAnd WdryRepresent different all wet respectively
With the weight of dry-spinning cortina, as a result as shown in Figure 6.
Test example 2
This test example carries out vitro characterization, the evaluation of animal et al. Ke based on artificial intervertebral disk prepared by embodiment 3.
The vitro characterization of spinning film, specific experiment method such as test example 1.
(1) cell is evaluated, and specific experiment method includes：
Nucleus pulposus and annulus fibrosis cells are extracted from rat disc.Comprise the following steps that；First by SD rats with 3% (wt/
Vol) yellow Jackets 1ml 100g-1Anaesthetized, dissection rat take out interverbebral disc, will be separated into each interverbebral disc nucleus pulposus and
Two parts of fibrous ring, are shredded with scissors；The digestion point respectively under 37 DEG C of environment with typeⅡ Collagen enzyme (0.3%wt/vol)
Nucleus pulposus (6 hours) and fibrous annulus tissue (9 hours) are solved, is filtered to remove not with nylon wire (100m BD, Biosciences) afterwards
The tissue of digestion, by cell suspending liquid and centrifuge (1000rpm, 3min) harvesting.With containing 10%FBS (hyclone,
Gibco), 1%PS (Pen .- Strep, Gibco) DMEM/F12 (Dulbecco's Modified Eagle Media：
Nutrient Mixture F-12, Gibco) at 37 DEG C, 5%CO2Cultivated under environment.Every 3 days with 0.25% trypsase
Passed on.
Before cell culture, to spinning film, per one side, ultraviolet irradiation is thoroughly sterilized for 30 minutes respectively for we, and
Sodium alginate soln and calcium sulphate soln autoclaving 30 minutes at 121 DEG C.Before cultivating cell on spinning film, we use fine
Even protein solution immersion spinning film surface, to promote adhesion of the cell in material surface.
We show influence of the PPC-III spinning film of pattern to AFCs taxises for research difference, by AFCs with 105~
106ml-1Density is inoculated on the orderly and unordered spinning film upper surfaces of PPC- III respectively, again 37 DEG C afterwards, 5% titanium dioxide
Cultivated 3 days under carbocyclic ring border, nucleus and F- actin filaments use Hoechst 33342 and the phalloidines of acti-TM 488 respectively
Dyeing.With confocal laser scanning microscope cellular morphology.We pass through the cell of assessing cell density to analyze on spinning film
Multiplication rate, cell density are defined as the number of the nucleus of every given surface product dyeing.
By using the angle of orientation of the nucleus by Hoechst dyeing under Image J 40 × multiplication factors of software analysis
Degree, to analyze the degree of order of cell on different substrates.Cell orientation angle represents major axis the receiving relative to orientation of cell body
The angle in the direction of rice fiber, and the degree of order of the lower expression cell of cell angle is higher.In order to analyze, we are by AFCS's
Angle with 10 ° be gradient be divided into 9 groups of 10~90 grade, when nucleus angle within 10 ° it is considered that cell is ordered into arranging
's.
In order to show the multilayered structure of fibrous ring, the spinning that direction is+30 ° and -30 ° is used difference by us respectively
Fluorescence is dyed, the artificial AF observed by laser scanning confocal microscopy sectional view picture.Concrete operation step is as follows：1) quiet
Before Electrospun, prepare respectively mixed with DiO (green) and two kinds of PPC-III solution of DiD (red) dyestuff；2) our PPC-
III electrospun membranes are cut into nanofiber relative to the major axis of band respectively with the film of+30 ° and -30 ° direction arrangements；3) heap
Folded two bands with opposite fibers orientation, and simultaneously manufacture of intraocular IVD multilayer AF regions (are schemed in mandrel by them
10a)。
(2) animal interior evaluating, specific experiment method include：
Preparing the artificial intervertebral disk of the fibrous ring based on orderly PPC-III and the nucleus pulposus composition based on marine alga acid gel
Afterwards, we carry out disc replacement in the position of rat (SD, male, 250g) rat tail bone 3/4.We are before surgery with 3%
(wt/vol) yellow Jackets are with 1ml 100g-1Dosage SD rats are anaesthetized, performed the operation afterwards in gnotobasis
Operation.Replanted after excision natural intervertebral disc into artificial intervertebral disk.The space of interverbebral disc can be fixed on after being implanted into order to ensure IVD
On, we fix rat tailses backbone with external fixation device.We with BioSpec70/20USR systems (Bruker,
Biospin Magnetic resonance imaging (MRI) image of tail bone) is obtained, obtains high-resolution T2 weighting sequence (resolution ratio：137m×
47m × 1mm) after the implantation 0,1 and 3 month check IVD form.
Our histopathological analysis TE-IVD and the combination of autologous tissue, we utilize hematoxylin eosin staining
TE-IVD and autologous spinal tissues contact interface are observed, is taken pictures afterwards with just putting microscope and be scanned.
Dyeing and flaking step are as follows:
We carried out histologic analysis when 1,3 month to TE-IVD and control, put to death 6 each experimental groups respectively
Animal is to carry out histopathological analysis.Step is as follows：
(1) it is fixed：The muscle and tendon fiber of afterbody is removed, is immersed in 2% paraformaldehyde solution 2 days with fully fixed
Tissue
(2) decalcification：By sample ultrapure water it is clean after, be placed in tris- hydrochloride buffers progress decalcification processing, know
Road tissue, which softens, to be cut into slices
(3) cut into slices：By the sample FFPE after decalcification, the thin slice of 5 μ m thicks is then cut into, we utilize bush
Essence-eosin stains observation TE-IVD and autologous spinal tissues contact interface, taken pictures afterwards with just putting microscope and be scanned.
Although present invention has been a certain degree of description, it will be apparent that, do not departing from the spirit and scope of the present invention
Under the conditions of, the appropriate change of each condition can be carried out.It is appreciated that the invention is not restricted to the embodiment, and it is attributed to right
It is required that scope, it includes the equivalent substitution of each factor.
Claims (10)
1. a kind of three-dimensional artificial total spinal disc, it is characterised in that the interverbebral disc includes：
The anisotropic artificial fiber ring built using orderly spinning；With
Artificial nucleus.
2. interverbebral disc according to claim 1, it is characterised in that orderly spinning forms angle described in the artificial fiber ring
Degree is respectively 0~90 ° of scope, is most preferably+30 ° and -30 ° of the long band of strip spinning around axle curling composition cyclic structure, ring
Fiber is into aligning in interior same layer, and the fiber direction in adjacent two layers is opposite.
3. interverbebral disc according to claim 1 or 2, it is characterised in that the material of the artificial fiber ring is selected from next
Kind is a variety of：PCL, PLGA and collagen；
Preferably, the material of the artificial fiber ring is the mixture of PCL, PLGA and collagen；
It is highly preferred that the quality proportioning of PCL, PLGA and collagen is 2~4 in the mixture:2~3:1, further preferably
For 4:2:1、2:2:1、3:3:1 or 4:3:1, most preferably 3:3:1.
4. according to interverbebral disc according to any one of claims 1 to 3, it is characterised in that the artificial nucleus passes through based on sea
Marine alga gel structure prepared by mosanom and calcium sulfate.
5. according to the preparation method according to interverbebral disc according to any one of claims 1 to 4, it is characterised in that methods described
Comprise the following steps：
(1) by PLGA, PCL and collagen be dissolved in hexafluoroisopropanol prepare spinning before liquid；
(2) electrostatic spinning is carried out to liquid before the spinning described in step (1), and is prepared in order using the roller collection device rotated
Spinning；
(3) the orderly spinning obtained in step (2) is cut to strip, it is in strip to make the major axis of spinning orientation and strip,
Then two layers of spinning membrane stack is gathered into folds, then rolls to form multilayer concentric circular ring structure around circular shaft, the spinning per adjacent two layers
Silk is arranged in order respectively, and the artificial fiber ring is made；
(4) CaSO is mixed4Solution and sodium alginate soln, mixed solution is poured into nucleus pulposus template, cylindric nucleus pulposus gel is made；
(5) by the obtained artificial fiber ring in the obtained nucleus pulposus gel Embedded step (3) in step (4), it is made
The interverbebral disc.
6. according to the method for claim 5, it is characterised in that in the step (1), the concentration of liquid is before the spinning
10%w/v；And/or
Described PCL, PLGA and collagen mass ratio are 2~4:2~3:1；Preferably, described PCL, PLGA and collagen
Mass ratio be 3:3:1.
7. the method according to according to claim 5 or 6, it is characterised in that in the step (2), the electrostatic spinning mistake
Cheng Caiyong 17G syringe needles add voltage 15kV, 1mL h-1Feed speed carry out spinning；And/or
The linear velocity of the roller is 13m s-1。
8. the method according to according to any one of claim 5~7, it is characterised in that in the step (4),
The concentration of the CaSO4 solution is 0~0.1g/mL, and excellent is 0.01~0.03g/mL, most preferably 0.02g/mL；
The sodium alginate soln concentration is 1%~20%w/v, preferably 2%w/v~5%w/v, most preferably 3%w/v；
The volume ratio of CaSO4 solution and sodium alginate soln is 1 in the mixed solution:10~10:1, preferably 1:2~2:1,
Most preferably 1:1.
9. according to made from the according to any one of claims 1 to 4 or method according to any one of claim 5~8
Three-dimensional artificial total spinal disc is preparing the application of tissue engineering material.
10. application according to claim 9, the tissue engineering material is the material for triggering disease for intervertebral disc disorder
Material.
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