CN102989034A - Hydrogel applicable to neuroanastomosis and preparation method thereof - Google Patents
Hydrogel applicable to neuroanastomosis and preparation method thereof Download PDFInfo
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- CN102989034A CN102989034A CN2011102807350A CN201110280735A CN102989034A CN 102989034 A CN102989034 A CN 102989034A CN 2011102807350 A CN2011102807350 A CN 2011102807350A CN 201110280735 A CN201110280735 A CN 201110280735A CN 102989034 A CN102989034 A CN 102989034A
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Abstract
The invention discloses a hydrogel applicable to neuroanastomosis, wherein the concentration of poloxamer or derivative of the poloxamer in the hydrogel is 10% (W/V)-30% (W/V), and the concentration of biodegradable macromolecule and/or nutritional ingredient is 0.1% (W/V)-5% (W/V). The hydrogel united medical adhesive provided by the invention is applicable to the small-mesooecium neural anastomotic method, so that the seal performance of an anastomotic stoma can be increased, the orientated growth of the nerve can be promoted, and the problems of error aligning, crimping and the like of the neural functional clusters can be reduced.
Description
[technical field]
The present invention relates to be applied to the hydrogel of nerve anastomosis in the repairing of neural injury, be specifically related to a kind of hydrogel that is applied to little chamber neural anastomosis method and preparation method thereof.
[background technology]
Nerve suture around in the repairing of neural injury to the recovery extent important of postoperative limb function.Perineural reparation key is to repair the original seriality of nerve tract, and traditional nerve suture is the identical method of end terminal nerve adventitia.Along with the progress of technology, the method has reached higher level, yet its functional rehabilitation is but still not satisfactory.Trace it to its cause, the traditional neural anastomosis method of clinical discovery is difficult to the accurately nerve tract identical to connection function, and can be distorted, interlock between each bundle broken ends of fractured bone, even broken ends of fractured bone escape, or forms neuroma etc., has directly affected the recovery of function of nervous system; Secondly because the neural anastomosis mouth and around the scar tissue hypertrophy obviously quick than nerve tract, can invade anastomotic stoma and mechanically hinder the regenerating nerve aixs cylinder anastomotic stoma etc. of growing into.
To successfully regenerate behind the nerve damage, except preventing the Neuronal soma irreversible denaturation, most importantly guide Regenerating Axons to prolong by damage zone, and make Axonal growth cone seek, recognize target organ, to set up new aixs cylinder.Traditional nerve suture is difficult to guarantee above-mentioned factor, so various new method is arisen at the historic moment, its medium and small chamber neural anastomosis method is the focus of studying at present.
Little chamber neural anastomosis method requires to provide favourable microenvironment for injured nerve--and " regeneration chamber ", regeneration chamber are microenvironments that meets nerve growth as a relatively airtight space.Under the effect of neural far-end secretion active substance, the aixs cylinder of near-end regeneration selectively is directed in the identical endoneurial tube of far-end function in that neuranagenesis is indoor, avoid the nerve growth mistake, the sensory nerve inner mold tube of the prominent far-end of growing into of the motion of namely regenerating, can prevent that the surrounding tissue fibroblast from entering the neural broken ends of fractured bone and hindering neuranagenesis, help to improve the quality and quantity of axon regeneration, make the aixs cylinder of the regeneration target organ of growing into, form effectively and connect the recovery limb function.
Desirable regeneration chamber comprises good blood supply and can give full play to neurotrophic and tropism, to promote neuranagenesis and functional rehabilitation.But the regeneration chamber method of using at present comprises silica regeneration chamber, chitin regeneration room, adventitia oversleeve type regeneration room and little gap vein bridge joint regeneration room etc., also there are variety of issue or deficiency, for example: silica regeneration chamber non-degradable needs for the second time operation to take out silica gel tube; The chitin regeneration room has limited its extensive use slowly because of chitin vivo degradation speed; The identical operation requirements of adventitia oversleeve type regeneration room is strict, operation more complicated, the outer easy scarring of Membrane cover of postoperative; Little gap vein bridge joint regeneration room is softer because of little gap location, and inside lacks support, and pressurized becomes flat easily, in addition neural blindly growth, and the corresponding relation in the short time between the nearly far-end of nerve fiber is difficult to connect.
Summary of the invention
The technical problem to be solved in the present invention is the weak point for existing medium and small chamber neural anastomosis of nerve anastomosis method, a kind of hydrogel that is applied to nerve anastomosis and preparation method thereof is provided, utilizing this hydrogel Phase Transformation Characteristic to unite the bonding method uses, improve neural anastomosis quality and speed, realize safe and efficient neural anastomosis.
Through repeatedly experiment, the inventor has prepared a kind of hydrogel that is applied to nerve anastomosis, has solved the weak point of medium and small chamber neural anastomosis of existing nerve anastomosis method, and the technical solution used in the present invention is as follows.
A kind of hydrogel that is applied to nerve anastomosis, poloxamer or derivatives thereof concentration is 10% (W/V)-30% (W/V) in this hydrogel, and the concentration of biodegradable macromole and/or nutritional labeling is 0.1% (W/V)-5% (W/V).
Above-mentioned poloxamer is polyoxyethylene poly-oxygen propylene aether, i.e. α-hydrogen-ω hydroxyl poly-(oxygen ethylene)
a-poly-(oxypropylene)
b-poly-(oxygen ethylene)
cBlock copolymer, structural formula are HO (CH
2CH
2O)
a(OCHCH
3CH
2)
b(CH
2CH
2O)
c, a and c are that 2～150, b is 15～67 in copolymer.
Above-mentioned biodegradable macromole comprises albumen, polysaccharide, soluble starch and derivant thereof.
Above-mentioned nutritional labeling refers to that medical science is known and has nutrition or the composition of the growth that excites nerve, comprises hormone, cytokine, somatomedin, stimulating factor, chemotactic factor, interleukin, vitamin, aminoacid, interferon, monosaccharide and disaccharide, oligosaccharide, organic monoacid.
Above-mentioned organic monoacid comprises citric acid, tartaric acid, fumaric acid, boric acid, acetic acid.
Poloxamer concentration is 15% (W/V)-25% (W/V) in the above-mentioned hydrogel, and biodegradable macromole and/or nutritional labeling concentration are 0.25% (W/V)-1% (W/V).
Above-mentioned hydrogel is frozen into solid gel in that to be mobile macromolecule glue below 37 ℃ aqueous between 37 ℃-45 ℃.
A kind of preparation of gels method that is applied to nerve anastomosis, under sterile working's environment, the poloxamer or derivatives thereof is scattered in the water for injection, dissolving, add biodegradable macromole and/or nutritional labeling, jolting forms hydrogel to fully dissolving, poloxamer or derivatives thereof concentration is 10% (W/V)-30% (W/V) in the hydrogel, and the concentration of biodegradable macromole and/or nutritional labeling is 0.1% (W/V)-5% (W/V).
The hydrogel of above-mentioned preparation further lyophilization forms lyophilized powder, is sealed in the cillin bottle and preserves, and injects before use water for injection, and slight jolting recovers to form hydrogel.
The invention solves the deficiency of existing medium and small chamber neural anastomosis of nerve anastomosis method, have the following advantages: (1) hydrogel of the present invention is united the medical adhesive application, avoids little chamber neural anastomosis method operation complexity, material non-degradable, little gap location inside of existing report to lack the deficiencies such as support and easy pressurized modification.(2) hydrogel of the present invention associating medical adhesive is used, and has increased the airtight performance of anastomotic stoma, promotes neural oriented growth, and the mistake that has reduced function of nervous system's bundle is to, the problem such as curling.(3) use hydrogel of the present invention, for neuranagenesis has been created a good nutrition environment, guarantee neural Fast Growth.(4) use hydrogel of the present invention, the plane of structure that can not limit the regeneration chamber is long-pending, avoids cicatrization.
The specific embodiment
Below further specify the present invention from specific embodiment.
Embodiment one, preparation contain Pluronic/Lutrol F 108, hetastarch and recombinant human somatropin's hydrogel
Present embodiment selects Pluronic/Lutrol F 108, biodegradable macromole hetastarch and nutritional labeling recombinant human somatropin to be raw material, the preparation hydrogel.
Preparation of gels: take by weighing 3.0g Pluronic/Lutrol F 108,0.09g hetastarch 130/0.4 and 0.01g recombinant human somatropin, add 10ml water for injection and dissolve the formation hydrogel fully, lyophilization becomes lyophilized powder, and fill seals in aseptic cillin bottle.Face time spent adding 10ml water for injection, slight jolting forms hydrogel.
Embodiment two, preparation contain the hydrogel of PLURONICS F87 and fumaric acid
It is raw material that present embodiment is selected PLURONICS F87 and nutritional labeling fumaric acid, the preparation hydrogel.
Preparation of gels: take by weighing 2.5g PLURONICS F87 and 0.5g fumaric acid, jolting or be stirred to fully dissolving and form hydrogel in 20 ℃ of water-baths, fill in asepsis injector, sealing.
Embodiment three, preparation contain poloxamer188, tyrosine and human albumin's hydrogel
It is raw material that present embodiment is selected poloxamer188, biodegradable macromole human albumin and nutritional labeling tyrosine, the preparation hydrogel.
Preparation of gels: take by weighing 2g poloxamer188,0.2g human albumin and 0.05g tyrosine and be scattered in the 10ml water for injection, be stirred to fully dissolving, form hydrogel, fill seals in asepsis injector.
Embodiment four, preparation contain the hydrogel of poloxamer188 derivant and neurotrophic factor
Poloxamer has multiple derivant structure, and it is raw material that present embodiment is selected the heparinization derivant of poloxamer188 and nutritional labeling neurotrophic factor, the preparation hydrogel.
Synthesizing of poloxamer188 heparinization derivant: take by weighing poloxamer188 (relative molecular weight M=12000, a=c=101 wherein, b=56) 12g, in a round-bottomed flask, the succinic anhydride that adds 2mmol, the 4-dimethylaminopyridine of 2mmol and 0.55ml triethylamine, and be dissolved in the 200ml dioxane, stirring reaction spends the night, getting terminal is the poloxamer of carboxyl, take it as reactant, utilize 1-ethyl-3,3-dimethyl aminopropyl carbodiimide (EDC)/N-hydroxyl is in imidodicarbonic diamide (NHS) method, the low molecular sodium heparin that adds 10g, stirring reaction 24h.Product was through bag filter dialysis 3 days, and products therefrom obtains pressed powder by lyophilization, obtains poloxamer188 heparinization derivant.
Preparation of gels: take by weighing the above-mentioned synthetic poloxamer188 heparinization derivant of 1g, be scattered in the 10ml water for injection, add the 0.01g neurotrophic factor, fully dissolving, filled with solution seals in disposable sterilized injector.
Embodiment five, gelation temperature are measured
The hydrogel that present embodiment obtains take embodiment 1-4 is measured gelation temperature as object.
Experimental technique: embodiment 1-4 obtains hydrogel and respectively gets 5ml, spends the night 4 ℃ of lower placements, then progressively heats up, and the Accurate Measurement hydrogel varies with temperature k value, and each sample determination three times is averaged.
Experimental result: the gelation temperature of the hydrogel that embodiment 1-4 obtains is respectively 37.8 ℃, 37.6 ℃, 38.0 ℃, 38.2 ℃.Therefore, the hydrogel that embodiment 1-4 obtains possesses and is being flowing liquid state shape below 37 ℃, is frozen into the characteristic of solid gel between 37 ℃-45 ℃.
Embodiment six, bonding method are carried out the identical experiment of animal nerve
Present embodiment is investigated the application performance of hydrogel associating medical adhesive of the present invention in nerve anastomosis.
Experimental technique: 20 of healthy male Wistar rats, body weight 250g～300g, be divided at random two groups, be bonding group (experimental group of hydrogel associating medical adhesive of the present invention) and stitching group (using the matched group of sewing), every group 10, adopting the rats with left sciatic nerve is that repairing model is tested.Rats by intraperitoneal injection 1% pentobarbital sodium (40mg/kg) is anaesthetized, get left side strand rear portion stringer otch, cut skin, separating muscle, appear left sciatic by musculus lateralis externi gap behind the thigh, cut off sciatic nerve apart from piriformis outlet 1.5cm place with double-edged razor blade at sciatic nerve, bonding group: excision fraction nerve makes neural broken ends of fractured bone adventitia leave 2～3mm gap, the hydrogel of embodiment four preparations is filled into two broken ends of fractured bone of cross-section nerve, use accurate temperature fixed point heater two broken ends of fractured bone are heated to 40-41 ℃, hydrogel in the cross-section neural broken ends of fractured bone forms solid, with two broken ends of fractured bone under operating microscope with accurately involutory, be coated with the medical adhesive Fibrin Glue in the junction, left and right sides Fibrin Glue solidified in 30 seconds, reduce the temperature to 37 ℃ of anastomotic part, finish nerve anastomosis, the postoperative limbs are fixing.The stitching group: carry out neural broken ends of fractured bone para-position take neural vascular surface as anatomic landmark under operating microscope, adopt 11/0 nylon wire adventitia to sew up 4 pins, the postoperative limbs are unfixing.
The regenerating nerve performance is observed: each group was got 8 rats and was carried out after electric physiological detection finishes 8 weeks of postoperative, draw materials in neural anastomosis place, bind neural two ends with 3/0 silk thread, stretching, be fixed on the little plank, place in the 10% neutral formalin solution and fix, use paraffin embedding, transverse section is done at each 1cm place of near, the far away section of anastomotic stoma, longitudinal section is done in the stage casing, carries out histological observation and graphical analysis through HE and Luxolfastblue dyeing.All the other every group 2 rats are got rapidly anastomotic stoma distally sciatic nerve, drop into immediately in-4 ℃ 2.5% the glutaraldehyde and fix 2 hours, then from wherein cutting 1mm
3Fritter, with fixing behind 1% osmic acid, dehydration of alcohol step by step, the Epon embedding, ultrathin section dyes transmission electron microscope observing regenerating nerve ultrastructure through aluminum uranium is two.In addition, 8 weeks of postoperative, each group was got 8 again intraperitoneal anesthesias of rat, appear the bilateral sciatic nerve, carry out electric physiological detection with intelligent bio signal display and processing system, sciatic incubation period of determination experiment animal both sides and bring out the wave amplitude of current potential, experiment with computing side sciatic nerve nervus motorius latent period delay ratio.
Experimental result: the regenerating nerve histological observation finds that the bonding group of aixs cylinder distortion of using hydrogel associating medical adhesive is lighter, and cicatrization is less, and the distortion of contrast stitching group aixs cylinder is more obvious, is spiral, and cicatrization is more.Transmission electron microscope observing shows, use hydrogel and unite myelinated nerve fiber marshalling in the bonding group of regenerating nerve of medical adhesive, myelin structure normal, neurofilament and microtubule and structure of mitochondria reappear in the aixs cylinder, myelinated nerve fiber is evacuated in the contrast stitching group regenerating nerve, the myelin thickness is inconsistent, and neurofilament, micro-tubular structure blur in the aixs cylinder, visible cavity sample degeneration.The sciatic nerve electrophysiologic study found that it is fast to compare the bonding group of nerve conduction velocity of shining stitching group application hydrogel associating medical adhesive, and the duration of hiding is little, and the nervus motorius latent period delay has obvious improvement.
In the above-described embodiments, only the present invention has been carried out exemplary description, but those skilled in the art can carry out various modifications to the present invention after reading present patent application in the situation that does not break away from the spirit and scope of the present invention.
Claims (9)
1. hydrogel that is applied to nerve anastomosis, it is characterized in that: poloxamer or derivatives thereof concentration is 10% (W/V)-30% (W/V) in this hydrogel, and the concentration of biodegradable macromole and/or nutritional labeling is 0.1% (W/V)-5% (W/V).
2. a kind of hydrogel that is applied to nerve anastomosis according to claim 1, it is characterized in that: described poloxamer is polyoxyethylene poly-oxygen propylene aether, i.e. α-hydrogen-ω hydroxyl poly-(oxygen ethylene)
a-poly-(oxypropylene)
b-poly-(oxygen ethylene)
cBlock copolymer, structural formula are HO (CH
2CH
2O)
a(OCHCH
3CH
2)
b(CH
2CH
2O)
c, a and c are that 2～150, b is 15～67 in copolymer.
3. a kind of hydrogel that is applied to nerve anastomosis according to claim 1, it is characterized in that: described biodegradable macromole comprises albumen, polysaccharide, soluble starch and derivant thereof.
4. a kind of hydrogel that is applied to nerve anastomosis according to claim 1, it is characterized in that: described nutritional labeling refers to that medical science is known and has nutrition or the composition of the growth that excites nerve, comprises hormone, cytokine, somatomedin, stimulating factor, chemotactic factor, interleukin, vitamin, aminoacid, interferon, monosaccharide and disaccharide, oligosaccharide, organic monoacid.
5. a kind of hydrogel that is applied to nerve anastomosis according to claim 4, it is characterized in that: described organic monoacid comprises citric acid, tartaric acid, fumaric acid, boric acid, acetic acid.
6. a kind of hydrogel that is applied to nerve anastomosis according to claim 1, it is characterized in that: poloxamer concentration is 15% (W/V)-25% (W/V) in the described hydrogel, and biodegradable macromole and/or nutritional labeling concentration are 0.25% (W/V)-1% (W/V).
7. a kind of hydrogel that is applied to nerve anastomosis according to claim 1 is characterized in that: described hydrogel is frozen into solid gel in that to be mobile macromolecule glue below 37 ℃ aqueous between 37 ℃-45 ℃.
8. preparation of gels method that is applied to nerve anastomosis, it is characterized in that: under sterile working's environment, the poloxamer or derivatives thereof is scattered in the water for injection, dissolving, add biodegradable macromole and/or nutritional labeling, jolting is to fully dissolving, form hydrogel, poloxamer or derivatives thereof concentration is 10% (W/V)-30% (W/V) in the hydrogel, and the concentration of biodegradable macromole and/or nutritional labeling is 0.1% (W/V)-5% (W/V).
9. a kind of preparation of gels method that is applied to nerve anastomosis according to claim 8, it is characterized in that: prepared hydrogel further lyophilization forms lyophilized powder, be sealed in the cillin bottle and preserve, inject before use water for injection, slight jolting recovers to form hydrogel.
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| CN109364293A (en) * | 2018-10-24 | 2019-02-22 | 温州医科大学 | A kind of nerve damage portion packing material and preparation method thereof |
| CN109464465A (en) * | 2018-10-24 | 2019-03-15 | 温州医科大学 | A kind of islet cell transplantation hydrogel and preparation method thereof |
| CN111544069A (en) * | 2020-06-10 | 2020-08-18 | 叶晓峰 | Self-healing nerve anastomosis device |
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