CN102688076B - Nerve conduit and preparation method thereof - Google Patents
Nerve conduit and preparation method thereof Download PDFInfo
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- CN102688076B CN102688076B CN201110073822.9A CN201110073822A CN102688076B CN 102688076 B CN102688076 B CN 102688076B CN 201110073822 A CN201110073822 A CN 201110073822A CN 102688076 B CN102688076 B CN 102688076B
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Abstract
The invention discloses a nerve conduit and a preparation method thereof. The nerve conduit consists of an inner layer, an outer layer and at least one minitype cavity for storing a bioactive factor solution, wherein the inner layer is of a hydrophilic cell scaffold layer, and the outer layer is of a hydrophobic nerve conduit scaffold layer. The nerve conduit can further comprise a transition layer between the inner layer and the outer layer. The preparation method of the nerve conduit comprises the steps of preparing the inner layer by adopting an electrostatic spinning method, then adding the material for preparing the cavity, then preparing the outer layer, and taking out or dissolving the material for preparing the cavity, thus obtaining the nerve conduit. The nerve conduit has the minitype cavity, so that bioactive factors can be loaded by a manner of injection, soaking and the like as required before operation, thus not only leading the production quality to be easily controlled, but also being capable of greatly improving the survival rate of the bioactive factors, more efficiently promoting the regeneration of nerves, and enhancing the restoration effect of nerves.
Description
Technical field
The invention belongs to bio-medical material and implantable medical devices field, be specifically related to a kind of nerve trachea and preparation method thereof.
Background technology
Nervous system is one of topmost organ in human body, and it is controlling the sense organ motor function of human body.Various wounds as compressing, drawing-off, tear, cut off and other factors will cause neural part or all of damage as ischemia, tumor etc., thereby cause afunction and other nervous system disease.The reparation of damaged nerve and the reconstruction of function are one of mankind's difficult problems of waiting to capture.
Perineural neuron axon can extend under proper condition, grows damaged region, reaches neuranagenesis object.By means of the particularly development of microneurosurgery of neurosurgery, the reparation of nerve injury and regeneration have become possibility.The neural recovery technique of at present research and application clinically mainly contains three kinds, directly coincide, neural transplantation (autologous or allosome) and nerve trachea reparation.Directly coincide is directly the near end of dialysis nerve, body end far away to be carried out to operation stitching, only be confined to shorter neurotmesis (being less than 8mm), this is because nerve does not stretch function, the regeneration that the tension force that stitching produces can affect the nerves, therefore also helpless to the neurologic defect of long pause, and its curative effect acceptance rate is only 50%.Neural transplantation meeting causes losing for district function of nervous system, not enough to large thicker neurologic defect source of supply, and has the problem of second operation.And heteroplastic transplantation is still needed and is solved immunosuppressant problem.Directly coincide and neural transplantation also exists broken ends of fractured bone sensory nerve and Motor nerve fibre connects problem of misalignment.Due in the traumatology department field, repairing of neural injury is to sew up by nerve end end, but because peripheral nerve is mixed nerve, and the current science discrimination method that can distinguish quickly and accurately neural broken ends of fractured bone sensory nerve and Motor nerve fibre in operation that also lacks, even if apply the capable perineurial suture of meticulous microsurgical technique, be also difficult to avoid after nerve end end is sewed up, because of the misorientation docking of sensation, Motor nerve fibre, and the curative effect that affects the nerves and sew up, the recovery of the function that affects the nerves.
It is the study hotspot that current neuranagenesis is repaired that nerve trachea is repaired (bridge joint art), is tissue engineering, materialogy, biology, the common large focus of paying close attention to of medical circle.Chinese scholars is verified in recent ten years, and nerve trachea substitutes the feasibility that neurologic defect is repaired in autotransplantation.Because nerve has certain Regeneration and Repair ability, by conduit, induce, for the near end of damaged nerve, body end far away, put up a bridge, guide neural direction of regeneration, can make the shorter neuranagenesis reparation of defect length.In recent years, have scholar to advocate to stay the gap of 2 ~ 3mm between the neural broken ends of fractured bone, due to neural chemotaxis, be conducive to make near-end Sensory nerve fibre and Motor nerve fibre respectively nerve fiber corresponding to far-end dock, thereby improve neural repairing effect.
Than other repairing of neural injury method, adopt nerve trachea that the multiple advantage of neuranagenesis can be provided: the two ends of temporarily fixing and support damaged nerve in neuranagenesis; Guide neuronic aixs cylinder axial growth, avoid external and form neuroma; For neuranagenesis provides a relatively isolated microenvironment, the enriching nerve required neurotrophic factor of regenerating, reduces cell entry, prevents the formation of cicatrix; Be conducive to Sensory nerve fibre and Motor nerve fibre correctly nerve fiber corresponding to far-end dock, improve neural repairing effect.
Material for the preparation of nerve trachea is mainly divided into non-nervous tissue, non-biodegradable material and Biodegradable material.Non-nervous tissue's material mainly comprises duct of Arantius, arterial, amniotic duct, skeleton pipe, musculomembranous tube etc., the main feature of these materials is that to contain basement membrane similar to the cell based counterdie of schwann cell, for schwann cell, move into condition is provided, but these materials easily subside after ischemia, hypoplasia, formation lock scar tissue, hypertrophy and adhesion etc.Non-biodegradation shaped material was studied neuranagenesis situation as silica gel tube, polyethylene, polyvinyl fluoride etc. are once used to prepare nerve trachea, Nondegradable due to conduit, after neuranagenesis completes, conduit is still intactly stayed regeneration site, this may make regenerating nerve fibrosis, cause chronic nerve compression and cause inflammation, thereby its long-term effect is not satisfactory, application is clinically restricted.The two is all inadvisable.Degradation material is the focus of current nerve trachea research, present Research from current nerve trachea, mainly by various biocompatibility and degradable materials, as bovine collagen albumen, polylactic acid, chitosan etc., be processed as hollow pipe or the built-in fiber parallel with axle, sponge etc. therein again, near end and the body end far away of damaged nerve, put up a bridge, builds one and be conducive to the microenvironment that regeneration function is brought into play, stop growing into of connective tissue around, induction is neural regenerates along duct direction.In repair process, tube material is also degraded and is absorbed by organism gradually.And take this type of material as matrix inject before by physical absorption, microcyst, chemical bonding, use etc. mode on material in conjunction with various neuranagenesis promoter, as albumen, neural cell adhesion albumen, nerve growth factor, ciliary neurotrophic factor, the Brain Derived Neurotrophic Factor etc. of growing up, to promote neural regeneration; Or carry out schwann cell or stem cell cultivation, with constructing tissue through engineering approaches artificial nerve catheter.
Although oneself obtains many progress the research of nerve trachea bridge joint art, as Chinese patent CN100479785C(authorizes a day 2009.4.22) a kind of preparation method of double-layer artificial nerve catheter is disclosed, adopt the mode of reverse mould to prepare the ectonexine of nerve trachea.But also has suitable distance from replacing clinically nerve autograft reparation peripheral nerve defection.Its main cause is that the function that current tube material provides can't meet this accurately requirement of complicated physiological process of axon regeneration completely.
By electrostatic spinning technique, can prepare the bionical conduit of nanoscale.On the one hand, by the resulting fiber of method of electrostatic spinning, be nano level, the little several orders of magnitude of non-woven fabrics diameter that obtain than traditional method; Can adjust intensity, hardness, degradation speed, pipe thickness, the diameter of conduit, the character such as the distribution of aperture hole, material by technological parameter on the other hand.
The open day 2009.5.27 of Chinese patent CN101439205A() disclose a kind of nerve trachea, it has shell-cored structure, and sandwich layer is bioactive ingredients, and shell is Biodegradable material, by coaxial electrostatic spinning method, prepares.This nerve trachea along with the degrading activity material of material can be controlled release, but in nerve reparation early stage, shell fiber can not be degraded as support, so that bioactie agent can not well discharge, and does not reach the object of reparation.The open day 2009.8.19 of Chinese patent CN101507842A() nerve trachea of the flexible compressive resistance of a kind of spiral type is disclosed, by acid fiber by polylactic wrapping on stainless steel tube, and take it as receiving system, by electrostatic spinning, prepare described nerve trachea.The open day 2009.9.30 of Chinese patent CN101543645A() disclose a kind of polycaprolactone (PCL) static spinning nerve conduit, internal layer is the reticulate vessel that high molecular degradable fiber is made, the outer PCL Sub-micro Fibers for adopting method of electrostatic spinning to prepare.These two patents are just prepared nerve trachea with synthesising biological material merely, although also there is certain repairing effect, poor for the functional repairing effect of nerve, generally can only accomplish growing into of nerve fiber cell.
Although these patents have all adopted electrostatic spinning technique to prepare nerve trachea, still difficulty becomes desirable nerve trachea.Desirable nerve trachea should possess following characteristics:
(1) be necessary for neural reparation required three dimensions is provided, will guarantee that nerve trachea has suitable intensity, consistency and elasticity, make nerve there is the passage of regeneration;
(2) can biodegradation: conduit in vivo transplantation site can exist long time, after neuranagenesis completes, degrades, do not need second operation to take out;
(3) material therefor must possess low cytotoxicity, slight local organization untoward reaction etc.;
(4) there is suitable degradation cycle: when nerve growth, keep corresponding intensity, hardness, with obstruction free nerve growth; On the other hand, require again after neuranagenesis completes, degraded as early as possible, in order to avoid pressuring nerve;
(5) simultaneously can be for nerve provides nutrient substance in degraded, accelerator nerve reparation;
(6) there is desirable bilayer or multiple structure: skin provides necessary intensity, play the tight structure that prevents that connective tissue from growing into and play barrier action simultaneously; Internal layer needs to have macroporous structure and high voidage, is conducive to the infiltration of bioactie agent, for blood capillary and fibrous tissue, grows into nutrition is provided;
(7) possible in the situation that, at nerve trachea internal layer implantable neural peripheral cell, such as Schwann cell, will more be conducive to neural reparation like this, and effect will be better.
In promoting the process of nerve trachea bridge joint art clinical practice, be starved of the nerve trachea biomimetic material of a kind of similar neural matrix membrane function of research, material itself had both had good moulding processability, simultaneously again can be longer for the regeneration of aixs cylinder provides guiding and Nutrition, to meet better the requirement of during nerve regeneration.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of nerve trachea is provided, this nerve trachea has that intensity hardness is suitable, degradable, suitable neurotrophy material can be provided, have desirable bilayer or multiple structure, have semipermeability, cost is lower, with short production cycle, preserve transportation easily, not with virus, without immunologic rejection or immunologic rejection effect feature extremely low, that have wide range of applications, meet well the requirement of during nerve regeneration.
Another object of the present invention is to provide the preparation method of described nerve trachea.
Above-mentioned purpose of the present invention is achieved by following technical solution:
A nerve trachea, comprises internal layer, skin and at least one for storing the cavity of bioactie agent solution, and the outer surface of described internal layer is covered with skin, and described cavity is between outer field inner surface and the outer surface of internal layer; The hydrophilic cytoskeleton layer of described internal layer for adopting method of electrostatic spinning to make; The hydrophobicity nerve conduit stent layer of described skin for adopting method of electrostatic spinning to make.
As a kind of preferred version, between described internal layer and skin, also has transition zone.Being the application's nerve trachea, can be to comprise internal layer, transition zone, skin and at least one is for storing the cavity of bioactie agent solution; The outer surface of described internal layer is covered with transition zone, skin successively, and described cavity is located between outer field inner surface and the outer surface of transition zone and/or between the outer surface of described internal layer and the inner surface of transition zone.
The form of described cavity can by inside and outside layer and/or internal layer, transition zone and/or skin, transition zone wrap up not with the totally-enclosed property cavity of opening or with the cavity of one or more openings.
During application, with the nerve trachea of the cavity of one or more openings, after injecting bioactie agent solution, adopt medical needlework or smear the conventional methods such as human body absorbable material the opening of cavity is sealed; Nerve trachea with totally-enclosed property cavity can directly be used after injecting bioactie agent solution.
The connecting layer of described transition zone for adopting method of electrostatic spinning to make the mixed solution of hydrophilic polymer and hydrophobic polymer.Described transition zone makes can be connected preferably and be unlikely to layering between internal layer and skin, and it is too lofty that aperture and changes in material are unlikely to, thereby has improved the effect of nerve trachea.Described transition zone, the single transition zone that can prepare for a kind of mixed solution of mixed proportion, or by the mixed solution of the multiple different proportion compound transition zone of preparation successively from inside to outside; In described compound transition zone, by the one deck that connects internal layer, to connecting outer field one deck, the hydrophilic polymer content ratio of transition zone declines gradually, and hydrophobic polymer content ratio rises gradually.
Described outer field aperture is 0.08 ~ 1 μ m, and the average pore size of described internal layer is 20 ~ 100 μ m.
Because human body cell diameter is on average at 10-20 μ m.Average pore size, below 3 μ m, can effectively prevent the connective tissue nerve trachea inside of growing into.The size distribution that electrostatic spinning fiber obtains depends on fibre diameter to a great extent, and when known fiber diameter reduces, aperture also reduces at the same time.According to the document of having delivered, fibre diameter is when 4 ~ 10 μ m, and aperture is 20 ~ 45 μ m.Bibliographical information, the average pore size of Static Spinning regenerated fibroin fiber supatex fabric can reach 2 μ m.Meanwhile, for the active substance such as nutrient substance are provided, on internal layer support, planting schwann cell is a possible selection.The tube wall of whole nerve trachea is semi-permeable.Aperture, more than 0.8 μ m, reaches and can allow nutrient substance to enter.Therefore, we are controlled at outer aperture between 0.08 ~ 1.0 μ m, both can prevent that bioactie agent was to exosmosis, can stop fibroblastic growing into again simultaneously, cause unnecessary adhesion.
At nerve trachea internal layer, for effectively induction blood capillary and fibrous tissue are grown into, especially schwann cell, for neuranagenesis length provides better nutrition and structure, this layer adopts the hydrophilic material of good biocompatibility, moreover by electrostatic spinning parameter adjustment, we are controlled at the average pore size of internal layer between 20 ~ 100 μ m.Be conducive to like this moving into of cell, adhere to, propagation and Growth and Differentiation.
In described cavity, can contain bioactie agent solution.Described bioactie agent solution can adopt the mode of preoperative injection to be expelled to cavity.
Described bioactie agent is one or more mixture in neurotrophic factor, neurogliocyte or medicine.
Described neurotrophic factor (neurotrophic factors, NTFs) refers to neurotrophy material (neurotrophins) and Neuronal Survival is had to the somatomedin of regulating action.The growth of neurocyte, existence, growth, migration and set up functional contact with other cell, or in the regrowth of during nerve regeneration and aixs cylinder, be all subject to induction, the regulation and control of neurotrophic factor.
Described neurotrophy material (neurotrophins), is preferably polypeptide, aminoacid, glycosaminoglycans, gelatin, glucocorticoid (glucocorticoids), il-1 (IL-1).Described polypeptide, aminoacid, glycosaminoglycans, gelatin has wide spectrum to adhere to and enrichment to somatomedin, can excite undifferentiated cell directed differentiation, has the reproducibility repair function of inducing machine soma.As gelatin can promote the formation of blood vessel blood capillary, can strengthen to nerve trachea around the supply of the nutrient substance of the aixs cylinder of i.e. spontaneous new growth.Described glucocorticoid, il-1 can strengthen the expression of the Different Nutrition factor in vivo.
Described somatomedin Neuronal Survival to regulating action, be preferably nerve growth factor (nerve growth factor, NGF), Brain Derived Neurotrophic Factor (brain-derived neurotrophic factor, BDNF), neurenergen 3 (neurotrophin-3 NT-3), neurotrophy material-4/5 (neurotrophin-4/5, NT4/5), neurotrophin-6 (neurotrophin-6, NT-6), ciliary neurotrophic factor (ciliary neurotrophic factor, CNTF) or glial cell line-derived neurotrophic factor (glia cell line-derived neurotrophic factor, GDNF).The existing document of the above factor has confirmed the facilitation to neural repairing growth all.NTFs has the function that stimulates multiple neuronal survival and differentiation, but the target cell group of the various factors not only has any different but also have intersection.NGF Main Function sensory neuron and sympathetic neuron and some cholinergic neuron of Basal forebrain portion in the period of development of neural crest origin, can induce sensation and noradrenergic neuron fiber to carry out larger extension, make local motion neurofibril also occur the phenomenon of germinateing.BDNF has and maintains and facilitation with growth regeneration the Development And Differentiation of polyesthesia neuron, cholinergic neuron, dopaminergic neuron and GABA serotonergic neuron.NT-3 has participated in spinal cord repair process.NT-3 and NT-4/5 are the trophic factors of sensory neuron, but are stoping using of the rear Motoneurons Death of damage, and NT-4/5 and BDNF have same effect.NT-3 can promote the growth of corticospinal tract after spinal cord injury, and can stop that in Rat Development, to damage the degeneration of Red nucleus neurons dead.
Described neurogliocyte is preferably schwann cell; Described medicine is preferably a kind of mixture that maybe can mix the several drugs of use in antibiotic, haemostatic medicament or anti-stick medicine.
As a kind of preferred version, described bioactie agent solution is preferably the antibiotic solution of 0.01 ~ 3% weight, the hemostasis of 0.001 ~ 3% weight and anti medicine, the bFGF solution of 0.001 ~ 0.5% weight.
In described bioactie agent solution, the content of described neurotrophic factor is preferably not higher than 10% weight of solution, and the density of contained neurogliocyte is preferably 10
5~ 10
9between individual/ml.
A preparation method for described nerve trachea, comprises the steps:
(1) prepare hydrophilic polymer solution; Prepare hydrophobic polymer solution;
(2) with the hydrophilic polymer solution that step (1) makes, by electrostatic spinning, prepare internal layer;
(3) the insoluble material horizontal for the preparation of cavity is fixed on to the upper surface that step (2) is prepared internal layer;
(4) preparation skin on the inner layer outer surface preparing in step (3) by electrostatic spinning, the outer hydrophobic polymer solution that adopts step (1) to make of preparation; By insoluble material being taken out from cross section in the ethanol of the sample immersion 70%-100% of preparation, obtain described nerve trachea.
The sample of preparation is dipped in ethanol, can makes sample softening, be convenient to the taking-up of insoluble material.
A preparation method for described nerve trachea, comprises the steps:
(1) prepare hydrophilic polymer solution; Prepare hydrophobic polymer solution; Preparation solubility gel;
(2) adopt and be with reeded rotor as electrostatic spinning receiving system;
(3) hydrophilic polymer solution is made to the reeded internal layer of tool by method of electrostatic spinning described being with on reeded rotor; In the groove of internal layer, apply solubility gel;
(4) outer in the internal layer one side preparation that scribbles solubility gel by electrostatic spinning, the outer hydrophobic polymer solution that adopts step (1) to make of preparation; The gel applying is dissolved, obtain described nerve trachea.
A preparation method for described nerve trachea, comprises the steps:
(1) prepare hydrophilic polymer solution; Prepare hydrophobic polymer solution; The mixed solution of preparing hydrophilic polymer and hydrophobic polymer;
(2) with the hydrophilic polymer solution that step (1) makes, by electrostatic spinning, prepare internal layer;
(3) the internal layer upper surface making in step (2) is prepared transition zone by electrostatic spinning, prepares the mixed solution that transition zone adopts the described hydrophilic polymer of step (1) and hydrophobic polymer; Insoluble material horizontal is fixed on to the outer surface of transition zone;
Or
To be fixed on insoluble material horizontal the outer surface of the internal layer that step (2) makes; Then on inner layer outer surface, by electrostatic spinning, prepare transition zone;
Prepare transition zone and adopt hydrophilic polymer that step (1) makes and the mixed solution of hydrophobic polymer;
(4) preparation skin on the transition zone outer surface preparing in step (3) by electrostatic spinning, the outer hydrophobic polymer solution that adopts step (1) to make of preparation; By insoluble material being taken out from cross section in the ethanol of the sample immersion 70%-100% of preparation, obtain described nerve trachea.
A preparation method for described nerve trachea, comprises the steps:
(1) prepare hydrophilic polymer solution; Prepare hydrophobic polymer solution; Preparation solubility gel; The mixed solution of preparing hydrophilic polymer and hydrophobic polymer;
(2) adopt and be with reeded rotor as electrostatic spinning receiving system;
(3) hydrophilic polymer solution is made to the reeded internal layer of tool by method of electrostatic spinning described being with on reeded rotor;
(4) in the groove of internal layer, apply solubility gel, by electrostatic spinning, in internal layer one side that scribbles solubility gel, prepare transition zone;
Or directly in the reeded side of internal layer tool, prepare the reeded transition zone of tool by electrostatic spinning, in the groove of transition zone, apply solubility gel;
Prepare transition zone and adopt hydrophilic polymer that step (1) makes and the mixed solution of hydrophobic polymer;
(5) preparation skin on the outer surface of the transition zone preparing in step (4) by electrostatic spinning, the outer hydrophobic polymer solution that adopts step (1) to make of preparation; The gel applying is dissolved, obtain described nerve trachea.
Cavity is prepared in acting as of described insoluble material, and described insoluble material is preferably draw point.
The nerve trachea that adopts insoluble material to prepare is the nerve trachea of the cavity with one or more openings.
Rotor with groove of the present invention, can be the conventional reeded rotor of being with on cylindrical rotor surface, can be also that the cross section that a part obtains of pruning on conventional cylindrical rotor is rotund rotor.
In general, conventional rotor is columniform (cross section is for circular), so nerve trachea prepared by method of electrostatic spinning is columniform.
And the cross section of the rotor that the part of pruning of the present invention obtains is subcircular.With respect to conventional rotor, the part of pruning is described groove.The conduit internal layer and/or the transition zone that while adopting the described rotor with groove as electrostatic spinning receiving system, make are also rotund, then by by solubility gel coating in the above, can be cylindrical the shape adjustments of internal layer and/or transition zone, prepare so again after skin, can obtain conventional cylindrical nerve trachea.
The nerve trachea that employing is prepared with groove rotor, water or organic solvent can enter the inside of conduit, dissolve gel layer, thereby obtain with by the nerve trachea of inside and outside layer and/or the totally-enclosed property cavity that internal layer, transition zone and/or skin, transition zone wrapped up.
Described solubility gel can or be dissolved in the gel of organic solvent for water miscible gel.As a kind of preferred version, described solubility gel is preferably the hydrogel that polysaccharide polymer, poltpeptides or synthetic high molecular weight hydrophilic polymer are prepared from; Described polysaccharide polymer is preferably starch, cellulose, alginic acid, hyaluronic acid or chitosan; Described poltpeptides is preferably collagen, polylysine or poly-L-glutamic acid; It is poly-for acrylamide that described synthetic high molecular weight hydrophilic polymer is preferably polyacrylic acid, polymethylacrylic acid, polyacrylamide or poly-N-.
Described hydrophobic polymer solution is that hydrophobic polymer is dissolved in the solution that solvent obtains; Described hydrophilic polymer solution is that hydrophilic polymer is dissolved in the solution that solvent obtains;
Described hydrophobic polymer is any one or a few mixture in hydrophobic polyurethane, polylactic acid, pla-pcl, polyglycolic acid, polyethylene terephthalate, polyhydroxy-alkanoate class, polyurethanes or Merlon;
Described hydrophilic polymer is Polyethylene Glycol, PHBV, poly butyric alkyl caproate, poly phosphate, polyvinyl alcohol, polyoxy ethane, collagen protein, gelatin, chitosan, modification of chitosan, starch, cellulose, modified cellulose, gelatin, fibrin, fibroin, the peptide polymer of elastin mimicry, alginic acid, chondroitin sulfate, heparin, agar, any one or a few mixture in glucosan or alginic acid;
Described solvent is the mixture of any one or several arbitrary proportion in formic acid, acetic acid, ethanol, acetone, dimethyl formamide, dimethyl acetylamide, oxolane, dimethyl sulfoxide, hexafluoroisopropanol, trifluoroethanol, dichloromethane, chloroform, methanol, chloroform, diox, HFC-143a, trifluoroacetic acid or water.
While utilizing natural material as nerve trachea raw material, in its degraded, can also play the effect of supply nutrient substance.
As a kind of preferred scheme, the macromolecular material of more preferably hydrophobic PLLA and poly-epsilon-caprolactone copolymerization of described hydrophobic polymer, both mass ratioes are 30:70 ~ 70:30, and number-average molecular weight is 150000 ~ 500000, are dissolved in hexafluoroisopropanol or dichloromethane;
Or the copolymer of hydrophobic polylactic acid and polyglycolic acid (PLGA), both mass ratioes are 10:90, number-average molecular weight is 350000, is dissolved in hexafluoroisopropanol or dichloromethane.
As a kind of preferred scheme, described hydrophilic polymer is hydrophilic gelatin, fibroin more preferably; The mass ratio of described gelatin and fibroin is preferably 20:80 ~ 80:20, and hydrophilic polymer is 3 ~ 15% of solution gross mass;
Or hydrophilic chondroitin sulfate and hyaluronic acid, described chondroitin sulfate and hyaluronic mass ratio are preferably 20:80 ~ 80:20, and hydrophilic polymer is 3 ~ 15% of solution gross mass.
Described solvent preferred solvent is the mixture of any one or several arbitrary proportion in formic acid, acetic acid, ethanol, acetone, dimethyl formamide, dimethyl acetylamide, oxolane, dimethyl sulfoxide, hexafluoroisopropanol, trifluoroethanol, dichloromethane, chloroform, methanol, chloroform, diox, HFC-143a, trifluoroacetic acid or water.
The described mass ratio with hydrophilic or hydrophobic material and solvent is the conventional ratio in existing electrostatic spinning technique.
The electrostatic spinning process parameter of described hydrophobic polymer solution is preferably as follows: the speed of micro-injection pump is 0.1 ~ 5 ml/hour, and the voltage of high tension generator is 5 ~ 45kV, and the receiving range of receiving system is 10 ~ 30 centimetres;
The electrostatic spinning process parameter of described hydrophilic and hydrophobic polymer mixed solution is preferably as follows: the speed of micro-injection pump is 0.1 ~ 8 ml/hour, and the voltage of high tension generator is 5 ~ 40kV, and the receiving range of receiving system is 12 ~ 25 centimetres;
The electrostatic spinning process parameter of described hydrophilic polymer solution is preferably as follows: the speed of micro-injection pump is 0.1 ~ 10 ml/hour, and the voltage of high tension generator is 5 ~ 35kV, and the receiving range of receiving system is 10 ~ 25 centimetres.
For making nerve trachea reach intensity and hardness requirement, preferably preparation has internal layer and the skin that several different materials form simultaneously, makes more than total hot strength reaches 1MPa.
Compared with prior art, the present invention has following beneficial effect:
(1) the present invention utilizes specific neurotrophic factor, combining nano bionic bracket material, attract neural axon growth, carry out reparative regeneration, solved the development barrier that current nerve trachea faces, for neural recovery provides required three dimensions, guaranteed that nerve trachea has suitable intensity, consistency and elasticity, made nerve there is the passage of regeneration;
(2) the nano bionic nerve trachea of neurotrophic factor used herein itself, not containing living cells composition, is not used foreign cell, has exempted all multi-risk Systems that therefore bring immunologic rejection, virus disseminating, disease propagation;
(3) material used in the present invention be at present verified to the nontoxic safe biologic material of human body, be artificial material, can not bring all multi-risk Systems of immunologic rejection, virus disseminating, disease propagation, can not bring other toxic action yet;
(4) nerve trachea integral material of the present invention is semipermeability, does not allow cell to pass through, and allows nutrient substance to pass through, the fibrosis of having avoided cell to bring, and nutrition is by having accelerated again axon growth, neural reparation;
(5) nerve trachea of the present invention is not owing to containing living cells composition, and material source is abundant, and cost is lower, avoided natural material source not enough, and cost is high, and the shortcoming of modification complexity is stored transportation simply;
(6) the preparation method processing step of nerve trachea of the present invention is simplified, production time is short, can effectively avoid product in the course of processing to be polluted, and product quality is easy to control, product standard easily realizes, and product can be realized low cost, high efficiency industrialization is produced;
(7) nerve trachea of the present invention has good mechanical strength, supports suture needle, and automatic safe degraded guarantees that material keeps intensity and hardness during nerve has obtained repairing again, and this normally carries out neural reparation, avoids fibrosis, the phenomenons such as nerve compression;
(8) nerve trachea of the present invention has micro-cavities, compare with the nerve trachea product of traditional structure, can be by mode on demand before operation as loading bioactie agents such as injection, immersions, not only make production quality be easy to control, and can greatly improve the survival rate of bioactie agent, promote more efficiently neural regeneration, because the nerve trachea of traditional structure in making all needs various bioactie agents directly to mix with organic solvent, cause activity decreased or the forfeiture of bioactie agent; Promote more efficiently neural regeneration; In addition, the anti hydrophobic layer that the hydrophilic layer that voidage is high and voidage are low makes the bioactie agent stable release of energy when early stage, nerve trachea was not degraded in cavity, strengthens neural repairing effect.
Accompanying drawing explanation
Fig. 1 is the schematic cross-section of the application's nerve trachea;
Fig. 2 is the schematic cross-section of the application's nerve trachea;
Fig. 3 is the described schematic cross-section with groove rotor;
Fig. 4 is the schematic cross-section of conventional rotor.
The specific embodiment
Below in conjunction with embodiment, further explain the present invention, but embodiment does not limit in any form to the present invention.
Reagent and device used in embodiment unless otherwise specified, is all to adopt common reagent and the device in this area.
In Fig. 1,2,1 is cavity, and 2 is internal layer, and 3 is outer, and 4 is the passage for nerve growth, and 5 is transition zone;
Described in the application, with the cross section of groove rotor, see Fig. 3, wherein, 6 is rotor; The schematic cross-section of conventional rotor as shown in Figure 4, wherein, after 7 part is pruned, forms the band groove rotor described in Fig. 4.
embodiment 1
(1) select hydrophilic gelatin and fibroin albumen, both mass ratioes are 70:30, solvent is formic acid, and spinning liquid mass fraction is 15%, spinning liquid is added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is 8 mls/hour, receiving range is 10 centimetres, and voltage is 20 kV, opens electrostatic spinning machine, carry out spinning, make the cytoskeleton internal layer of average 800 ~ 1000 nm of fibre diameter;
(2) select the macromolecular material of hydrophobic PLLA and 6-caprolactone copolymerization, both mass ratioes are 50:50, number-average molecular weight is 310000, with gelatin and fibroin albumen quality than the mixture for 70:30 as solute, be dissolved in that in hexafluoroisopropanol, to obtain mass fraction be 12% spinning liquid, and the mass ratio 25:75 of foundation (PLLA and 6-caprolactone: gelatin and fibroin albumen), 50:50, 75:25 prepares three kinds of different mixed solutions, regulating the speed of micro-injection pump is 5 mls/hour, regulating the voltage of high tension generator is 30kV, regulating the receiving range of receiving system is 15 centimetres, and by the mode of electrostatic spinning, spin on the rotor with cytoskeleton internal layer successively from high to low by the content of gelatin and fibroin albumen, make the transition zone of the average 700 ~ 800nm of fibre diameter,
(3) select the macromolecular material of hydrophobic PLLA and 6-caprolactone copolymerization, both mass ratioes are 50:50, number-average molecular weight is 310000, be dissolved in that in hexafluoroisopropanol, to obtain mass fraction be 10% spinning liquid, above, spin transition zone on place the draw point that two diameters are 0.05mm and fix, then above-mentioned solution is added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is 3 mls/hour, regulating the voltage of high tension generator is 30 kV, and regulating the receiving range of receiving system is 15 centimetres; Open electrostatic spinning machine, continue spinning on transition zone, finally obtaining pipe thickness is the nerve trachea skin of 0.2mm;
Clean, the sample of preparation is immersed to the ethanol of 70%-100%, pump draw point, get final product to obtain described nerve trachea, sterilizing, packing.This nerve trachea hot strength is 8MPa.
embodiment 2
(1) select hydrophilic chondroitin sulfate and hyaluronic acid, both mass ratioes are 70:30, take formic acid as solvent, and spinning liquid mass fraction is 12%, spinning liquid is added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is 10 mls/hour, receiving range is 12 centimetres, and voltage is 20 kV, opens electrostatic spinning machine, in columniform rotor spinning, make the cytoskeleton internal layer of the average 1000 ~ 1500nm of fibre diameter;
(2) select hydrophobic pla-pcl, with chondroitin sulfate and the hyaluronic acid mass ratio mixture that is 70:30 as solute, be dissolved in that in hexafluoroisopropanol, to obtain mass fraction be 10% spinning liquid, and the mass ratio 25:75 of foundation (pla-pcl: chondroitin sulfate and hyaluronic acid), 50:50, 75:25 prepares three kinds of different mixed solutions, regulating the speed of micro-injection pump is 5 mls/hour, regulating the voltage of high tension generator is 25 kV, regulating the receiving range of receiving system is 15 centimetres, and by the mode of electrostatic spinning, spin on the rotor with cytoskeleton internal layer successively from high to low by chondroitin sulfate and hyaluronic content, make the transition zone of the average 800 ~ 1000nm of fibre diameter,
(3) select hydrophobic PLLA and 6-caprolactone, both mass ratioes are 50:50, for copolymerized macromolecule material, number-average molecular weight is 250000, be dissolved in that in hexafluoroisopropanol, to obtain mass fraction be 8% spinning liquid, above, spin transition zone on place the draw point that two diameters are 0.05mm and fix, then above-mentioned solution is added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is 3 mls/hour, regulating the voltage of high tension generator is 25kV, and regulating the receiving range of receiving system is 17 centimetres; Open Static Spinning, obtain nerve trachea;
Clean, the sample of preparation is immersed to the ethanol of 70%-100%, pump draw point, get final product to obtain described nerve trachea, sterilizing, packing.This nerve trachea hot strength is 10MPa.
embodiment 3
(1) preparation is as shown in Figure 4 with the rotor of groove;
(2) select hydrophilic chondroitin sulfate and hyaluronic acid, both mass ratioes are 70:30, spinning liquid mass fraction is 12%, spinning liquid is added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is 10 mls/hour, and receiving range is 12cm, and voltage is 20 kV, carry out spinning, make the cytoskeleton internal layer of the average 1000 ~ 1500nm of fibre diameter; Then at groove, apply water miscible gelatin gel;
(3) select hydrophobic PLLA and 6-caprolactone, both mass ratioes are 50:50, for copolymerized macromolecule material, number-average molecular weight is 310000, with the ratio of chondroitin sulfate and the hyaluronic acid gross mass mixture that is 70:30 as solute, be dissolved in that in hexafluoroisopropanol, to obtain mass fraction be 12% spinning liquid, and the mass ratio 25:75 of foundation (PLLA and 6-caprolactone: chondroitin sulfate and hyaluronic acid), 50:50, 75:25 prepares three kinds of different mixed solutions, regulating the speed of micro-injection pump is 5 mls/hour, regulating the voltage of high tension generator is 30kV, regulating the receiving range of receiving system is 15 centimetres, and by the mode of electrostatic spinning, spin on the rotor with cytoskeleton internal layer successively from high to low by the content of chondroitin sulfate and hyaluronic acid gross mass, make the transition zone of the average 800 ~ 1000nm of fibre diameter,
(4) select hydrophobic PLLA and 6-caprolactone, both mass ratioes are 50:50, for copolymerized macromolecule material, number-average molecular weight is 310000, be dissolved in that in hexafluoroisopropanol, to obtain mass fraction be 10% spinning liquid, then above-mentioned solution added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is 3 mls/hour, regulating the voltage of high tension generator is 30kV, and regulating the receiving range of receiving system is 15 centimetres; Open Static Spinning, prepare nerve conduit stent layer;
(5) groove being applied to water miscible gelatin gel dissolves and obtains described nerve trachea;
Clean sterilizing, packing.This nerve trachea hot strength is 8MPa.
embodiment 4
(1) preparation is as shown in Figure 4 with the rotor of groove;
(2) selecting hydrophilic chondroitin sulfate and hyaluronic acid mass ratio is 70:30, take trifluoroethanol as solvent, spinning liquid mass fraction is 20%, spinning liquid is added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is that 8 mls/hour of receiving ranges are 10 centimetres, and voltage is 15kV, opens electrostatic spinning machine, carry out spinning, make the cytoskeleton internal layer of the average 1000 ~ 1500nm of fibre diameter; Then at groove, apply water miscible gelatin gel.
(3) selecting the ratio of hydrophobic PLGA(lactic acid and hydroxyacetic acid is 10:90), for copolymerized macromolecule material, number-average molecular weight is 350000, with chondroitin sulfate and the hyaluronic acid mass ratio mixture that is 70:30 as solvent, be dissolved in that in trifluoroethanol, to obtain mass fraction be 17% spinning liquid, and the mass ratio 25:75 of foundation (PLGA: chondroitin sulfate and hyaluronic acid), 50:50, 75:25 prepares three kinds of different mixed solutions, regulating the speed of micro-injection pump is 3.5 mls/hour, regulating the voltage of high tension generator is 25 kV, regulating the receiving range of receiving system is 15 centimetres, and by the mode of electrostatic spinning, spin on the rotor with cytoskeleton internal layer successively from high to low by the content of chondroitin sulfate and hyaluronic acid gross mass, make the transition zone of the average 800 ~ 1000nm of fibre diameter,
(4) selecting the ratio of hydrophobic PLGA(lactic acid and hydroxyacetic acid is 10:90), for copolymerized macromolecule material, number-average molecular weight is 350000, be dissolved in that in trifluoroethanol, to obtain mass fraction be 14% spinning liquid, then above-mentioned solution is added in the syringe of electrostatic spinning device, regulating the speed of micro-injection pump is 3ml/h, and regulating the voltage of high tension generator is 25kV, and regulating the receiving range of receiving system is 20 centimetres; Open Static Spinning, prepare nerve conduit stent layer;
(5) groove being applied to water miscible gelatin gel dissolves and obtains described nerve trachea;
Clean sterilizing, packing.This nerve trachea hot strength is 11MPa.
embodiment 5 rabbit zooperies
The artificial nerve catheter that adopts embodiment 1 to make is tested.Experimental rabbit body weight 2-5kg, age 6-8 month, male and female were regardless of, totally 10.Preserved skin after auricular vein anesthesia, is placed in animal on special-purpose operating table ventral decubitus.The large leg outer side of left lower extremity, sciatic nerve traveling is in greater trochanter and humerus ectocondyle line rear approximately 1 centimeters, and take this line mid point is mid point, stringer, long 7 centimetres are cut skin, the separated thigh lateral muscle group of little curved forceps, adjusts operating microscope, focusing peroneal nerve, with separated this nerve of brain book, prop up, the nerve that exposes 4 centimeter length, cuts 3cm, artificially manufactures neurologic defect model.
Select 3 millimeters of diameters, the artificial nerve catheter of long 4 centimetres, No. 6 silk threads, round needle, apart from 5 millimeters of catheter tips, entering pin, at neural far-end, through neural, by conduit the inner, entering pin, conduit outside goes out pin, be U font and sew up, this neurofixation can not be rotated, and tie a knot after being inserted in nerve trachea.With round needle, No. 1 silk suture muscle film, No. 1 wire discontinuous sewing for skin.Clinical follow 1 year, and carry out the evaluation of behavioristics, morphology, electric physiological behavior.
Wherein before operation, the mode by injection loads bioactie agent, and in bioactie agent solution, the content of neurotrophic factor is 8%, and the density of neurogliocyte is 10
5~ 10
9between individual/ml, antibiotic content is 1%, and the content of haemostatic medicament is 1%, and the content of bFGF is 0.2%.
Result of study shows: postoperative art limb can not land, the behavior disorder of postoperative 2 months animals starts to recover, acupuncture sole has retraction reaction, postoperative 4 months without obvious obstacle, within postoperative 1 year, without heavy burden in the situation that, recovered normal, trunk sensory evoked potential (SEP) and Motion Evoked Potential (MEP) recover.After observing for 1 year, get the art standard laid down by the ministries or commissions of the Central Government originally, formalin is fixedly done HE dyeing, see that nerve fiber recovered its seriality, the nerve trachea of implanting is degraded, the nerve fiber of regeneration is intensive, it is more neat to arrange, neural and conduit intersection is without cicatrix, the nerve fiber nothing connective tissue proliferation of Shu Shengchang that affects the nerves around, but have a small amount of macrophage.
embodiment 6 sheep zooperies
The artificial nerve catheter that adopts embodiment 3 to make is tested.Experiment sheep body weight 30-40kg, male and female are regardless of, totally 4.After anesthesia, preserved skin is placed on special-purpose operating table, ventral decubitus, fixing limbs.Under operating microscope, focus on common peroneal nerve, expose the common peroneal nerve of 7cm, the 5cm that denervates, artificially manufactures neurologic defect model.Choosing diameter is 6mm, the artificial nerve catheter that 6cm is long, and No. 10 silk threads, at artificial nerve catheter end 5mm place inserting needle, are " U " groove part and close, and make neurofixation, can not rotate, and be enclosed within artificial nerve catheter inside.Clinical follow 1 year, and carry out the evaluation of behavioristics, morphology, electric physiological behavior.
Wherein before operation, the mode by injection loads bioactie agent, and in bioactie agent solution, the content of neurotrophic factor is 8%, and the density of neurogliocyte is 10
5~ 10
9between individual/ml, antibiotic content is 2%, and the content of haemostatic medicament is 2%, and the content of bFGF is 0.3%.
Result of study shows: postoperative art limb can not land, the behavior disorder of postoperative 2 months animals starts to recover, within 4 months, acupuncture sole has retraction reaction, within postoperative 1 year, without heavy burden in the situation that, has recovered normal, and trunk sensory evoked potential (SEP) and Motion Evoked Potential (MEP) recover.After observing for 1 year, get the art standard laid down by the ministries or commissions of the Central Government originally, formalin is fixedly done HE dyeing, see that nerve fiber recovered its seriality, the nerve trachea of implanting is degraded, the nerve fiber of regeneration is intensive, it is more neat to arrange, nerve and conduit intersection are without cicatrix, and nerve fiber is around without the connective tissue proliferation of the Shu Shengchang that affects the nerves, and the macrophage of hypertrophy is less.
Claims (5)
1. a preparation method for nerve trachea, is characterized in that, described nerve trachea, comprises internal layer, skin and at least one is for storing the cavity of bioactie agent solution; The outer surface of described internal layer is covered with skin, and described cavity is between outer field inner surface and the outer surface of internal layer; The hydrophilic cytoskeleton layer of described internal layer for adopting method of electrostatic spinning to make; The hydrophobicity nerve conduit stent layer of described skin for adopting method of electrostatic spinning to make;
Its preparation method comprises the steps:
(1) prepare hydrophilic polymer solution; Prepare hydrophobic polymer solution; Preparation solubility gel;
(2) adopt and be with reeded rotor as electrostatic spinning receiving system;
(3) hydrophilic polymer solution is made to the reeded internal layer of tool by method of electrostatic spinning described being with on reeded rotor; In the groove of internal layer, apply solubility gel;
(4) outer in the internal layer one side preparation that scribbles solubility hydrogel by electrostatic spinning, the outer hydrophobic polymer solution that adopts step (1) to make of preparation; The gel applying is dissolved, obtain described nerve trachea.
2. the preparation method of nerve trachea as claimed in claim 1, is characterized in that, described outer field average pore size is 0.08 ~ 1 μ m, and the average pore size of described internal layer is 20 ~ 100 μ m.
3. the preparation method of nerve trachea as claimed in claim 1, is characterized in that, described bioactie agent is one or more mixture in neurotrophic factor, neurogliocyte or medicine.
4. the preparation method of nerve trachea as described in any one claim in claim 1 ~ 3, is characterized in that described hydrophobic polymer solution is that hydrophobic polymer is dissolved in the solution that solvent obtains; Described hydrophilic polymer solution is that hydrophilic polymer is dissolved in the solution that solvent obtains;
Described hydrophobic polymer is any one or a few mixture in hydrophobic polyurethane, polylactic acid, pla-pcl, polyglycolic acid, polyethylene terephthalate, polyhydroxy-alkanoate class, polyurethanes or Merlon;
Described hydrophilic polymer is Polyethylene Glycol, PHBV, poly butyric alkyl caproate, poly phosphate, polyvinyl alcohol, polyoxy ethane, collagen protein, chitosan, modification of chitosan, starch, cellulose, modified cellulose, gelatin, fibrin, fibroin, the peptide polymer of elastin mimicry, alginic acid, chondroitin sulfate, heparin, agar, any one or a few mixture in glucosan or alginic acid.
5. the preparation method of nerve trachea as described in any one claim in claim 1 ~ 3, the electrostatic spinning process parameter that it is characterized in that described hydrophobic polymer solution is as follows: the speed of micro-injection pump is 0.1 ~ 5 ml/hour, the voltage of high tension generator is 5 ~ 45kV, and the receiving range of receiving system is 10 ~ 30 centimetres;
The electrostatic spinning process parameter of described hydrophilic polymer solution is as follows: the speed of micro-injection pump is 0.1 ~ 10 ml/hour, and the voltage of high tension generator is 5 ~ 35kV, and the receiving range of receiving system is 10 ~ 25 centimetres.
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| CN103127548B (en) * | 2013-01-31 | 2014-09-10 | 东南大学 | Manufacture method of artificial nerve conduit for promoting nerve defect repair |
| CN103110436B (en) * | 2013-03-11 | 2015-05-13 | 刘亚平 | Nerve spacer in centrum |
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| CN105748171B (en) * | 2016-02-21 | 2017-09-15 | 新乡医学院 | Biological nerve duct |
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| CN107158467B (en) * | 2017-05-03 | 2019-09-10 | 武汉理工大学 | A kind of double-layer porous nerve trachea and preparation method thereof with directional guide function |
| CN108379655B (en) * | 2018-05-22 | 2020-06-30 | 中山大学 | Nerve graft with three-dimensional orientation structure and preparation method and manufacturing equipment thereof |
| CN108888384B (en) * | 2018-07-18 | 2021-03-26 | 广州迈普再生医学科技股份有限公司 | Tubular stent with double-layer structure and preparation method thereof |
| CN109513041B (en) * | 2018-12-29 | 2023-10-03 | 南通纺织丝绸产业技术研究院 | Nerve conduit with magnesium silk composite woven structure and preparation method thereof |
| CN109999222B (en) * | 2019-04-15 | 2021-08-13 | 大连工业大学 | Preparation method of nerve conduit material based on polyhydroxyalkanoate/sodium alginate electrospun nanofiber |
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