CN102836016A - Implantable degradable device for promoting nerve regeneration after peripheral nerve transplantation - Google Patents
Implantable degradable device for promoting nerve regeneration after peripheral nerve transplantation Download PDFInfo
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Abstract
The invention relates to an implantable degradable device for promoting nerve regeneration after peripheral nerve transplantation. The implantable degradable device is a hollow cylindrical device formed by folding two symmetrical semi-cylindrical components; dividing the inside of the cylindrical device into a plurality of independent small chambers for loading nerve regeneration promoting substances with different concentrations; the two ends of the cylindrical device are open, so that the peripheral nerve transplantation repair material can penetrate in from one end and penetrate out from the other end; the gap between the two semi-cylindrical components is sealed into a closed tubular structure by medical biological protein glue; the semi-cylindrical component is made of a degradable biocompatible material. The implantable degradable device has the advantages of simplicity, safety and high efficiency, can be used for loading various substances for promoting nerve regeneration, and enables the substances for promoting nerve regeneration to form concentration gradients according to the far end and the near end of a nerve and to surround the periphery of a peripheral nerve graft to form a microenvironment beneficial to the regeneration of peripheral nerve axons.
Description
Technical field
The present invention relates to provides a kind of embedded type device that promotes neuranagenesis behind the peripheral nerve graft, the device of neuranagenesis behind especially a kind of degradable promotion peripheral nerve graft.
Background technology
Peripheral nerve defection is repaired and reconstruction, is world's clinic study a great problem for over 100 years more than a hundred years.Along with socioeconomic fast development, the degree of mechanization increases, and traffic is flourishing day by day, and under the situation of movement of population multiplication, perineural damage is just risen hastily.Peripheral nerve injury all is mainly between twenty and fifty labour force, and labour force's permanent disability becomes heavy economy and the ethics burden of social development and family, restricts and hamper The development in society and economy.
The therapeutic effect of peripheral nerve injury is undesirable, and one of main difficult problem is do not have to occur behind the suitable material repairing nerve damage damaged.The most frequently used clinically graft materials is an autologous nerve; But the donor diameter is thin, and the quantity that can cut is very limited, is difficult to meet clinical needs; And can cause the neurologic defect that supplies the district new after drawing materials; Complication such as district's neuroma formation and corresponding delayed ischemic neurological deficits occur supplying, therefore, the development of peripheral nerve graft material is the emphasis problem in neural reparation field always.In recent years, the research institutions of many countries and enterprise has dropped into a large amount of human and material resources and fund is studied peripheral nerve repairing material.Known as ideal peripheral nerve timbering material should be able to for neuranagenesis provide best physics and chemistry and biology microenvironment; Comprise: (1) excellent biological compatibility (avirulence; Reduced immunogenicity, no teratogenesis carcinogenecity) and degradability, can be absorbed by body after neural the reparation.(2) have plasticity and certain mechanical strength, can protect regenerating nerve smoothly through the neurologic defect district; (3) have and the neural similar bionic three-dimensional supporting structure of repairing, support and the growth of guiding regenerating nerve; (4) component of material with constitute excellent biological compatibility; (5) the assurance neuranagenesis is repaired required nutrition supply, and the adjusting nerve growth is arranged in the timbering material, breaks up and promote the neurotrophic factor of neural reparation and tissue regeneration, improves the microenvironment of neuranagenesis, improves axonal regeneration speed.The nerve graft technology with good biocompatibility and imitation biochemistry of preparation is comparatively ripe at present, existing at home and abroad many patent applications.The nerve regeneration conduit that uses PLGA, chitosan and collagen protein Biodegradable material to process like Chinese patent 200910250344.7; 200910034583.9 a kind of catheter-like nerve graft of being made up of through the nanofiber of electrospinning process preparation polymer then is provided; Process a kind of high-artificial tissue engineering nerve repair material and the application's applicant's 20041002724.8 engineered nerve grafts etc. before this 200910020942.5 then use 1 collagen type, chitosan, gelatin.Yet single nerve trachea does not contain any bioactive substance, only is the physical channel of neuranagenesis, does not possess any biological activity, thus the poor effect of its reparation, particularly for the long section neurologic defect that more needs nutrient substance.But how to guarantee the required nutrition supply of neuranagenesis reparation; The nutrient substance that has support, guides neural reparation of promotion and tissue regeneration is provided; Improve the neuranagenesis microenvironment, and can form Concentraton gradient and instruct the neural axon guiding growth to be still a still unsolved difficult problem.Though can have the seed cell of BA at present through plantation on nerve graft; Be divided into the class Schwann cell that to secrete short nerve growth material (like Chinese patent 200410027223.3,200410027224.8,200410027221.4,200420045860.9,200420045859.6,200420045858.1,200420045857.7,200410027222.9 etc.) in vivo and in vitro in the environment or on timbering material, add various neurotrophic factors through it; Realize that through structure controlled release systems such as chemistry or biologies localized sustained slowly discharges (like Chinese patent 200410012856.3; 200410009429.3; 200610081506.5,200610150792.6 etc.).Though use seed cell; Through in the body or external evoked one-tenth type schwann cell; Also can secrete the trophic factors that is of value to neuranagenesis, can promote axon regeneration and myelin to form, but its secretory nerve fertile absorber have the timeliness limitation; And the treatment of stem cell relates to safety in utilization, problems such as standard and ethics.Up to now, except hematopoietic stem cell treatment hematopathy, the whole world does not have the stem-cell therapy of any one research and medical institutions to be accepted and evaluate as yet.China's Ministry of Public Health also clearly is included into stem cells technology " the 3rd type of medical skill " especially in " the medical skill clinical practice management method " of in March, 2009 issuing and implementation; Claim its " relate to great ethical issues, safety, effectiveness are still needed and further verified through the clinical experimental study of standard ".Therefore this cellular type organizational project is still far away from the clinical practice distance.And on timbering material, add various neurotrophic factors through technical methods such as chemistry or biologies; Specification requirement is higher on the one hand, makes complicacy, is difficult to guarantee the activity of neurotrophic factor; Be difficult to the standardization steady production; Majority can only add a spot of single neurotrophic factor on the other hand, and is quite limited to the effect of the promotion of neuranagenesis, so that limited use; Therefore how to be inclusive with the focus that multiple neurotrophic factor has been research at existing peripheral nerve graft material.If can on this material, there be simultaneously directed Concentraton gradient to distribute; Can guarantee the neurotrophy material of far-end q.s on the one hand; Prevent the too fast degeneration and the atrophy of target organ and muscle; Then can create an anisotropic cell growing environment on the other hand, make cell behavior that orientation and realization guiding take place.This will have important meaning for improving the peripheral nerve graft repairing effect.
Summary of the invention
The object of the present invention is to provide a kind of implanted degradable device that promotes neuranagenesis behind the peripheral nerve graft; That this device has is easy, safe, advantage efficiently; Can be used for loading multiple short neuranagenesis material; And will urge that the neuranagenesis material is far away according to nerve, near-end forms Concentraton gradient, be surrounded on peripheral nerve graft around, be formed with the microenvironment that is beneficial to the peripheral nerve axon regeneration.
A kind of implanted degradable device that promotes neuranagenesis behind the peripheral nerve graft of the present invention is the cylindrical device of being closed up the hollow that forms by two symmetric semi-cylinder assemblies; In said cylindrical device, be separated into a plurality of independently little chambers, be used to load the short neuranagenesis material of variable concentrations; The two ends of said cylindrical device are open, supply the peripheral nerve graft repair materials to penetrate and pass from the other end from an end; The gap of two semi-cylinder assemblies becomes the tubular structure of sealing through the Fibrin Glue sealing; Said semi-cylinder assembly is prepared by the degradable biological compatibility material.
In device of the present invention, short neuranagenesis material centers on the peripheral nerve graft repair materials of being inserted, and makes the peripheral nerve graft repair materials be enriched with multiple short neuranagenesis material on every side, is formed with the microenvironment that is beneficial to the peripheral nerve axon regeneration; Become tubular structure through the Fibrin Glue sealing, the place that needs peripheral nerve to repair in the implantable is as the device of peripheral nerve graft.And, owing to adopt the inner structure of separating the shape groove, can load various gelationus short neuranagenesis materials, accelerate axon regeneration speed; And can the neuranagenesis material is far away according to nerve with urging, near-end forms Concentraton gradient, nerve growth is played certain guide effect.
According to the further characteristic of device of the present invention, described semi-cylinder assembly has 40N/mm at least
2Fracture strength.Therefore, the tube of being processed by these semi-cylinder assemblies can provide certain machinery to support, can keep shape and be not easy to subside, thereby peripheral nerve graft in the protector prevents that fibrous scar tissue from growing into.
According to the further characteristic of device of the present invention, described semi-cylinder assembly has the porosity between 50%～80%, and has the micro-pore diameter between 5 μ m～50 μ m.Therefore, the semi-cylinder assembly has certain pore structure, helps the penetrating of nutrient substance, and blood capillary and fibrous tissue are grown into, and does not hinder the graft on every side in the device to obtain vascularization, also avoids loading in it short neuranagenesis material and exosmoses in a large number.
According to the further characteristic of device of the present invention, described semi-cylinder assembly is to be processed by following degradable biological compatibility material: chitosan, alginate, fibroin albumen, cellulose, collagen protein, chitin, chitosan, polylactic acid, polyglycolic acid, poly butyric fat, gather lactone, polyglycolic acid, aliphatic polyester, poly phosphate, Merlon, polyurethane and their copolymer.
According to the further characteristic of device of the present invention, described peripheral nerve graft repair materials is to be selected from: be used for synthetic material, natural biologic material or tissue engineering nerve that peripheral nerve defection is repaired.
According to the further characteristic of device of the present invention, said synthetic material is to be selected from following degradable biological compatibility material: polylactic acid, polyglycolic acid, poly butyric fat, gather lactone, polyglycolic acid, aliphatic polyester, poly phosphate, Merlon, polyurethane and their copolymer.
According to the further characteristic of device of the present invention, said natural biologic material be selected from derive from activated from body, remove the cell allogeneic or remove chitosan, alginate, fibroin albumen, cellulose, collagen protein, chitin, the chitosan of nerve, skeletal muscle, blood vessel, musculomembranous tube, mucosa, amniotic membrane and the non-activity of cell heterologous organism.
According to the further characteristic of device of the present invention, said tissue engineering nerve is kind of a tissue engineering bracket that is implanted with the spike daughter cell.
According to the further characteristic of device of the present invention, described seed cell is to be selected from: Schwann cell, medulla mesenchyma cell, fat mesenchymal stem cell, umbilical cord mesenchymal stem cells, NSC or induced multi-potent stem cells.
According to the further characteristic of device of the present invention, said short neuranagenesis material is to be selected from: neurotrophic factor, like nerve growth factor, BDNF, neurenergen family; Neural mitogen is like CNTF and interleukin-6; Non-neurotrophic factor is like fibroblast growth factor, leukocyte inhibitory factor, insulin like growth factor, epidermal growth factor, glial cell line-derived neurotrophic factor, platelet-derived growth factor, transforming growth factor; Perhaps their two or more combination.These short neuranagenesis materials can be participated in the material of peripheral nerve regeneration, adjusting and repair in trauma, and neuron and the aixs cylinder of protection behind the peripheral nerve injury arranged, and can promote axon regeneration, accelerate nerve repair function.
The implanted degradable device of neuranagenesis has following characteristics and advantage behind the promotion peripheral nerve graft of the present invention:
(1) a kind of device that loads short neuranagenesis material is provided,, makes peripheral nerve graft be enriched with multiple neuranagenesis material on every side, be formed with the microenvironment that is beneficial to the peripheral nerve axon regeneration as the device of the peripheral nerve graft that is used to implant.
The short neuranagenesis substance classes of (2) being loaded is unrestricted; Can select according to actual needs and can have than multicapacity; Break through use at present various complex technologys around nerve graft add the restriction of a spot of single short neuranagenesis material, also reduce simultaneously in previously complicated chemistry or the biological processing the short active influence of neuranagenesis material.
(3) the separation shape structure in this device can realize that short neuranagenesis material forms Concentraton gradient, might obvious facilitation be arranged to the aixs cylinder stretching, extension and the oriented growth of peripheral nerve regeneration.
(4) easy, the safety of whole processing technology, economy are efficient again, and the means of realization are comparatively easy, help large-scale production and clinical promoting the use of.
The specific embodiment
Embodiment one: the preparation of the implanted degradable device of neuranagenesis behind the promotion peripheral nerve graft of the present invention
The preparation material uses to gather (lactic-co-glycolic acid) copolymer (PLGA).
The preparation of semi-cylinder assembly: to gather (lactic-co-glycolic acid) copolymer (PLGA) (mol ratio GA: LA=20: 80) be raw material; It is dissolved in the dichloromethane; The NaCl that adds 200～300 microns of particle diameters does porogen (PLGA and NaCl mass ratio 1:9); Add lysine as alkaline conditioner in 5% ratio simultaneously, and mix homogeneously, with mixture film forming in particular manufacturing craft.Mixture in the mould at room temperature volatilizees in the fume hood naturally.After 96 hours, the semicolumn support is taken out in the demoulding, and it is moved on to vacuum drying oven, 37 ℃ of vacuum dryings 48 hours.Deionized water of replacing in per 4 hours the immersion of semicolumn material is equipped with in the 800ml large beaker of deionized water.Behind the deionized water wash 96 hours, the semicolumn material is taken out, 37 ℃ of dryings are 48 hours in drying baker.Then in vacuum drying oven, 37 ℃ of vacuum dryings 48 hours can obtain the PLGA assembly.
The assembling of assembly and use: in prepared semi-cylinder assembly, load short neuranagenesis material; Like gelatin nerve growth factor (NGF); And in neural proximal end concentration from high in the end changes over to different closely-spaced indoor; Insert after an allogeneic removes the cellular neural repair materials, two semi-cylinder assemblies are closed close, and use the bonding sealing of Fibrin Glue; Form a kind of tubular structure, make that allogeneic goes to be enriched with nerve growth factor (NGF) around the cellular neural repair materials.
Embodiment two: the preparation of the implanted degradable device of neuranagenesis behind the promotion peripheral nerve graft of the present invention
The preparation material is a chitosan.
The preparation of semi-cylinder assembly: the chitosan of getting 350 mg is dissolved in 3 mg/ml acetum 10ml, and evacuation leaves standstill 12 h, and chitosan solution is injected particular manufacturing craft.The sample direct-axis of injection molding in slow immersion profound hypothermia stranguria of cold type agent (liquid nitrogen), is carried out the gradient stranguria of cold type.The freezing type of silica gel tube of collagen protein-chitosan suspension that 10 cm are long is cut into the 2.0cm short segment and is positioned in the aluminum dish of pre-cooling, puts into Alphal-2 type freezer dryer, lyophilizing 24 h under-60 ℃, 100 m torr conditions.In the vacuum environment of freezer dryer, the solvent ice crystal in the freezing support distils, and obtains having the assembly of microcellular structure.Be warming up to 0 ℃ under the vacuum state and keep 6 h, continue to be warming up to 22 ℃ again and keep 30～60 min, remove vacuum, rise to room temperature, can make the chitosan assembly of dry forming.
The assembling of assembly and use: in prepared semi-cylinder assembly, load short neuranagenesis material; Like gelatin CNTF (CNTF); And change over to different closely-spaced indoor by from high in the end concentration in neural proximal end; After inserting a nerve trachea that gathers the preparation of lactone, two semi-cylinder assemblies are closed close, and use the bonding sealing of Fibrin Glue; Form a kind of tubular structure, make peripheral nerve repairing material be enriched with CNTF (CNTF) on every side.
Embodiment three: the preparation of the implanted degradable device of neuranagenesis behind the promotion peripheral nerve graft of the present invention
The preparation material is a collagen protein.
The preparation of semi-cylinder assembly: take by weighing collagen protein 150mg and be dissolved in the 0.05mmol/L glacial acetic acid solution; Stir 90min (18000r/min) under 4 ℃ of conditions; Behind the negative pressure evacuation in 4 ℃ of refrigerator overnight; Be injected into molding in the particular manufacturing craft after fully being mixed into the gel suspension, and with 2 * 10
-5The speed of m/s puts it in the aluminum dish of pre-cooling after getting in the condensing agent, and lyophilizing 48h in-40 ℃, 100mtorr condition makes the collagen protein assembly of drying and moulding.
The assembling of assembly and use: the assembling of assembly and use: in prepared semi-cylinder assembly, load short neuranagenesis material; Like gelatin glial cell line-derived neurotrophic factor (GDNF); And change over to different closely-spaced indoor by from high in the end concentration in neural proximal end; To insert one be seed cell with the Schwann cell, go cellular neural to be the tissue engineering nerve of support after, two semi-cylinder assemblies are closed close, and use the bonding sealing of Fibrin Glue; Form a kind of tubular structure, make this tissue engineering nerve repair material be enriched with glial cell line-derived neurotrophic factor (GDNF) on every side.
The particular manufacturing craft that is adopted in the foregoing description one to three is semicolumn structure (as: stainless steel bar or a glass tubing); The semicolumn concave surface has the n sheet to be separated to form n+1 layer structure (n=1,2,3 ...); Radius is 1～5mm; Length can be controlled arbitrarily, diameter and length mainly be according to the neural length that will repair and diameter decision, wall thickness 0.2～1mm.During concrete the use; But the gelatin short neuranagenesis material of variable concentrations injects in two semicolumnar different grooves in order; Then peripheral nerve graft (as removing cell allogeneic nerve repair material etc.) is placed short neuranagenesis material surface; Then two semicolumn assemblies are closed and close, the space between two groups uses Fibrin Glue to embrocate, can be closed fully after the drying.Make existing peripheral nerve graft be enriched with multiple neuranagenesis material on every side, be used for peripheral nerve defection and transplant material for repairing, to improve repairing effect.
According to experiment similar to the above embodiments; Those skilled in the art can adopt the degradable compatibility material of other biological to prepare the semi-cylinder assembly, for example alginate, fibroin albumen, cellulose, chitin, chitosan, poly butyric fat, gather lactone, polyglycolic acid, aliphatic polyester, poly phosphate, Merlon, polyurethane and their copolymer.
Through measuring, these semi-cylinder assemblies have 40N/mm at least
2Fracture strength, therefore, the support of certain machinery can be provided, peripheral nerve graft in the protector can be kept shape and be not easy to subside, and prevents that fibrous scar tissue from growing into.Simultaneously; These semi-cylinder assemblies have 50%～80% porosity, and need the micro-pore diameter between 5 μ m～50 μ m, therefore have certain pore structure; Help the penetrating of nutrient substance; Blood capillary and fibrous tissue are grown into, do not hinder the graft on every side in the device to obtain vascularization, also avoid loading in it short neuranagenesis material and exosmose in a large number.
In the neurologic defect reparation experiment, the peripheral nerve graft repair materials of inserting in the device of the present invention can be selected from: be used for synthetic material, natural biologic material or tissue engineering nerve that peripheral nerve defection is repaired around.Said synthetic material is to be selected from following degradable biological compatibility material: polylactic acid, polyglycolic acid, poly butyric fat, gather lactone, polyglycolic acid, aliphatic polyester, poly phosphate, Merlon, polyurethane and their copolymer.Said natural biologic material be selected from derive from activated from body, remove the cell allogeneic or remove chitosan, alginate, fibroin albumen, cellulose, collagen protein, chitin, the chitosan of nerve, skeletal muscle, blood vessel, musculomembranous tube, mucosa, amniotic membrane and the non-activity of cell heterologous organism.Said tissue engineering nerve is kind of a tissue engineering bracket that is implanted with the spike daughter cell.Described seed cell is to be selected from: Schwann cell, medulla mesenchyma cell, fat mesenchymal stem cell, human umbilical cord mesenchymal stem cells, NSC and induced multi-potent stem cells etc. possibly and be used to make up the seed cell of tissue engineering nerve to useful active of peripheral nerve regeneration.
The short neuranagenesis material of inserting in the device of the present invention can be selected from: neurotrophic factor, like nerve growth factor, BDNF, neurenergen family; Neural mitogen is like CNTF and interleukin-6; Non-neurotrophic factor is like fibroblast growth factor, leukocyte inhibitory factor, insulin like growth factor, epidermal growth factor, glial cell line-derived neurotrophic factor, platelet-derived growth factor, transforming growth factor; Perhaps their two or more combination.These short neuranagenesis materials can be participated in the material of peripheral nerve regeneration, adjusting and repair in trauma, and neuron and the aixs cylinder of protection behind the peripheral nerve injury arranged, and can promote axon regeneration, accelerate nerve repair function.
Embodiment four: the implanted degradable device of neuranagenesis is used for the damaged reparation experiment of the long section of macaque radial nerve behind the promotion peripheral nerve graft of the present invention.
Cut the long radial nerve of 4cm at the above 1cm of macaque upper arm radial nerve,deep starting point and cause the long neurologic defect of 5cm; The nerve end end is carried out labelling; Test group uses embodiment one prepared implanted degradable device to repair; The nerve autograft group is used the autologous nerve reparation of respective length, goes the cellular neural transplantation group to use the simple allogeneic of respective length to go the cellular neural reparation.Postoperative gram formula pin (diameter 1.5mm) is 135 ° of flexor of elbow joints fixedly.Dynamic observe August, and carry out tectology, electrophysiology and ethological evaluation.Each treated animal survival of postoperative is good, and the experimental group wound healing is good, does not find local redness, hydrops, ulceration, and untoward reaction does not appear in laboratory animal.8 months each treated animals of postoperative have all recovered to stretch the wrist function, and it is suitable with the nerve autograft group that test group is stretched the wrist movement range, is superior to the cellular neural transplantation group; The neuroelectricity physiological detection can find that all NAP exists; And the neural stimulation threshold of finding test group is suitable with the autologous nerve group; Be lower than the cellular neural group, peak swing and MNCV and autologous nerve group there was no significant difference, but be superior to the cellular neural group; Histology is presented in test group and the nerve autograft group; It is thus clear that the Schwann cell and the nerve fiber of a large amount of positive stainings; Nerve fiber marshalling, rule have a spot of positive staining Schwann cell and nerve fiber and arrangement mixed and disorderly and go cellular neural group nervous graft section far away S-100 albumen and neurofilament protein immunohistochemical staining to see.The above results shown according to implanted degradable device of the present invention repair the long section of macaque radial nerve damaged be feasible effectively, and be superior to traditional simple allogeneic and remove cellular neural.
Claims (10)
1. implanted degradable device that promotes neuranagenesis behind the peripheral nerve graft, it is characterized in that: said device is the cylindrical device of being closed up the hollow that forms by two symmetric semi-cylinder assemblies; In said cylindrical device, be separated into a plurality of independently little chambers, be used to load the short neuranagenesis material of variable concentrations; The two ends of said cylindrical device are open, supply the peripheral nerve graft repair materials to penetrate and pass from the other end from an end; The gap of two semi-cylinder assemblies becomes the tubular structure of sealing through the Fibrin Glue sealing; Said semi-cylinder assembly is prepared by the degradable biological compatibility material.
2. device according to claim 1 is characterized in that: described semi-cylinder assembly has 40N/mm at least
2Fracture strength.
3. device according to claim 1 is characterized in that: described semi-cylinder assembly has the porosity between 50%～80%, and needs the micro-pore diameter between 5 μ m～50 μ m.
4. device according to claim 1 is characterized in that: described semi-cylinder assembly is processed by following degradable biological compatibility material: chitosan, alginate, fibroin albumen, cellulose, collagen protein, chitin, chitosan, polylactic acid, polyglycolic acid, poly butyric fat, gather lactone, polyglycolic acid, aliphatic polyester, poly phosphate, Merlon, polyurethane and their copolymer.
5. device according to claim 1 is characterized in that: described peripheral nerve graft repair materials is to be selected from: be used for synthetic material, natural biologic material or tissue engineering nerve that peripheral nerve defection is repaired.
6. device according to claim 5 is characterized in that: said synthetic material is to be selected from following degradable biological compatibility material: polylactic acid, polyglycolic acid, poly butyric fat, gather lactone, polyglycolic acid, aliphatic polyester, poly phosphate, Merlon, polyurethane and their copolymer.
7. device according to claim 5; It is characterized in that: said natural biologic material is to be selected to derive from of the same race or the xenogenesis natural biological tissue, include active from body, remove the cell allogeneic or remove chitosan, alginate, fibroin albumen, cellulose, collagen protein, chitin, the chitosan of nerve, skeletal muscle, blood vessel, musculomembranous tube, mucosa, amniotic membrane and the non-activity of cell heterologous organism.
8. device according to claim 5 is characterized in that: said tissue engineering nerve is kind of a tissue engineering bracket that is implanted with the spike daughter cell.
9. device according to claim 8 is characterized in that: described seed cell is to be selected from: Schwann cell, medulla mesenchyma cell, fat mesenchymal stem cell, umbilical cord mesenchymal stem cells, NSC or induced multi-potent stem cells.
10. according to right 1 described device, it is characterized in that: said short neuranagenesis material is to be selected from: neurotrophic factor, like nerve growth factor, BDNF, neurenergen family; Neural mitogen is like CNTF and interleukin-6; Non-neurotrophic factor is like fibroblast growth factor, leukocyte inhibitory factor, insulin like growth factor, epidermal growth factor, glial cell line-derived neurotrophic factor, platelet-derived growth factor, transforming growth factor; Perhaps their two or more combination.
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