CN100539965C - Absorptive nervous catheter and manufacture method thereof - Google Patents
Absorptive nervous catheter and manufacture method thereof Download PDFInfo
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- CN100539965C CN100539965C CNB2004100671835A CN200410067183A CN100539965C CN 100539965 C CN100539965 C CN 100539965C CN B2004100671835 A CNB2004100671835 A CN B2004100671835A CN 200410067183 A CN200410067183 A CN 200410067183A CN 100539965 C CN100539965 C CN 100539965C
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Abstract
Disclose a kind of absorptive nervous catheter, it is made up of 80-120 weight portion chitosan and 10-30 part lactic acid substantially.Also disclose a kind of preparation method of absorptive nervous catheter, it comprises the steps: a) to provide the solution of chitosan in lactic acid, and this solution contains 80-120 weight portion chitosan and 10-30 part lactic acid; B) described solution evenly is coated on the mould rod, and heating makes it dry; D) product that obtains is dipped to the demoulding in the NaOH of 0.2-2N solution.
Description
Technical field
The present invention relates to a kind of absorptive nervous catheter of neurologic defect clinical repair around neurosurgery, plastic surgery, hands surgery, department of cerebral surgery and the orthopaedics etc. and manufacture method of this conduit of being used for.
Background technology
The treatment peripheral nerve injury is one of unsolved difficult problem still in the surgery field.The scientific research personnel is through long-term endeavour, and nerve injury reparation research aspect has obtained immense success around.
The key of peripheral nerve defection clinical repair is to seek a kind of neural biomaterial of repairing that is suitable for.Require this biomaterial to have good biocompatibility, when injected organism tissue is had no side effect, can be degraded in vivo and absorb and have characteristics such as certain hot strength and compression elasticity.
Chinese patent CN 1262961A discloses a kind of owing to the neural conduit of repairing, and it comprises chitosan, gelatin, glutaraldehyde, acetic acid, sodium hydroxide, poly-D-lysine.This conduit is that chitosan is dissolved in the acetum, adds gelatin and regulates (the seeing its claim 1 and 2) that pH value makes to this solution.
Chinese patent CN 1319379A discloses a kind of medical artificial nerve graft, and it comprises biological duct and is embedded in the interior fibrous framework (seeing its claim 1) of this biological duct.
But existing nerve trachea manufacture method has the defective that reactions steps is many, required time is long thereby manufacturing cost is high.
Therefore, this area also needs to develop a kind of absorptive nervous catheter easy and that have good biological intermiscibility and favorable elasticity intensity of making.
The content of invention
An object of the present invention is to provide a kind ofly react simple, step is few and make easily and the manufacture method of absorptive nervous catheter with low cost;
Another object of the present invention provides a kind of absorptive nervous catheter with good biocompatibility and favorable elasticity intensity.
Therefore, the invention provides a kind of absorptive nervous catheter, it is made up of 80-120 weight portion chitosan and 10-30 weight portion lactic acid substantially.
The present invention also provides a kind of manufacture method of described absorptive nervous catheter, and it comprises the steps:
A) provide the solution of chitosan in lactic acid;
B) described solution evenly is coated on the mould rod, and heating makes it dry;
C) repeating step b),, obtain the nerve trachea of molding until reaching required coating layer thickness;
D) with the nerve trachea drying of molding, being dipped to conduit subsequently in the NaOH of 0.2-2N solution can take off from the mould rod.
The present invention also provides the absorptive nervous catheter that is made by the invention described above method.
The accompanying drawing summary
Fig. 1 is that the nerve trachea of a better example of the present invention amplifies 5500 times microphotograph;
Fig. 2 is that Fig. 1 conduit amplifies 300 times microphotograph.
The specific embodiment
The manufacture method of absorptive nervous catheter of the present invention comprises the steps:
A) provide the solution of chitosan in lactic acid
Chitosan lactic acid solution of the present invention is dissolved in chitosan in the lactic acid and forms.The chitosan that is used to form chitosan lactic acid solution of the present invention is a deacetylation greater than 90% chitosan, and its deacetylation is preferably 92-99%, more preferably 95-99%.The viscosity of described chitosan is 500-800Mpas, is preferably 600-750Mpas.The chitosan that is used to prepare nerve trachea of the present invention is commercially available.For example it can be available from Norway Primex company.
The lactic acid that is used to form chitosan lactic acid solution of the present invention is the aqueous solution of lactic acid, better is that concentration is 1-10% (w/w), is more preferably the lactic acid aqueous solution of 1-5% (w/w).
Can earlier Powdered chitosan be dissolved in the lactic acid aqueous solution of 1-10% during configuration, fully stir and make it dissolving.In better example of the present invention, can be by removing by filter impurity and the vacuum removal of air bubbles in the solution.Be used for the method that filtering method can be this area routine.In a better example of the present invention, the lactic acid solution that uses 200 purpose screen filtrations to form.
In the lactic acid solution of described chitosan, the content of chitosan is the 80-120 weight portion, and the content of lactic acid is the 10-30 weight portion.When the content of chitosan and lactic acid was in this numerical range, the lactic acid solution of formation had certain viscosity, is enough to be coated on the mould rod form nerve trachea.
B) make nerve trachea
Get a mould rod, its external diameter equals the internal diameter of the nerve trachea of desire making.The chitosan lactic acid solution that forms above evenly is coated on this mould rod, and heating makes it dry, the formation nerve trachea.
The material that is used to make described mould rod is without particular limitation, as long as it has slick surface.The example that is fit to the described mould bar material of making has timber, plastics, rubber, glass, pottery etc.The external diameter of mould rod depends on the internal diameter of the nerve trachea that desire is made.
Be preferably, select and be coated with feed liquid to have the mould rod that good infiltrating material is made, the indefiniteness example of this material has glass, pottery etc.
In a better example of the present invention, described mould rod can be at the uniform velocity rotation of horizontal level, and the rotating speed of rotation is without particular limitation, can for example be 30-40rpm/min.
The method that is used to apply the chitosan lactic acid solution is without particular limitation, as long as described solution evenly can be coated on the mould rod.The indefiniteness example of described painting method for example have brush, spraying etc.
Can form coated film by drying after applying the chitosan lactic acid solution.It is without particular limitation to be used for exsiccant method, can be the dry or infrared dehydration for example of normal temperature air.The temperature of heat drying generally should be lower than 70 ℃, better is lower than 60 ℃ in order to avoid the coated film that damage forms.
In order to make the nerve trachea even tube wall and to have the thickness that required purposes requires, can repeat coating-drying steps at above-mentioned exsiccant coated film outer wall.Described coating-exsiccant number of times depends on the denseness of chitosan lactic acid solution and required nerve trachea pipe thickness.
After the nerve trachea molding, the nerve trachea that should be opposite on the mould rod carries out further intensive drying.Described exsiccant method can be a known method of the present invention.In a better example of the present invention, carry out drying with placing nerve trachea on the mould rod to put into vacuum drying system.
To be dipped to conduit through the nerve trachea of intensive drying in the NaOH of 0.2-2N solution subsequently can take off from the mould rod.
Will through intensive drying place nerve trachea on the mould rod to put into sodium hydroxide solution after, the nonesterified lactic acid of part can react with sodium hydroxide in the conduit, this moment conduit to become shallow milky translucent by transparent, pinning the mould rod with hands just can be with conduit demoulding from the mould rod.In general, conduit needed to soak in sodium hydroxide solution 1-1.5 hour.
Be washed till neutrality with the nerve trachea of distilled water after, deposit in the distilled water the demoulding.
The nerve trachea that makes with the inventive method is the elastic hose with certain hot strength, it is made up of 80-120 weight portion chitosan and 10-30 weight portion lactic acid substantially, and its hot strength is 5-7N, is preferably 5-6N, elastic extension is 50-70%, is preferably 50-60%.In a better example of the present invention, described nerve trachea pipe thickness is the 150-300 micron, is preferably the 180-300 micron.
Test shows that after 72 hours, its pH value is 6.8-7.2 to nerve trachea of the present invention with water extraction (37 ± 1 ℃); Cell toxicity test meets GB/T 16886.5-1997 4.5.1 regulation; Hypersensitive test meets GB/T16175.10-1996 4.5.2 regulation; Genetic toxicity test meets GB/T 16886.3-1997 4.5.5 regulation; Biodegradation test meets GB/T 16886.6-2001 4.5.4 regulation; Implantation Test meets GB/T16886.6-2001 4.5.3 regulation; Sterility test meets GB/T 16886.3-1997 4.5.5 regulation.
As shown in Figure 1, there be the irregular aperture of many diameters less than 1 μ m in the surface of nerve trachea of the present invention, these apertures have permeability, allow the micromolecule nutrient substance by aperture required nutrient substance so that neuranagenesis to be provided, the anastomotic stoma scar hyperplasia is avoided in the intrusion of fibroblast capable of blocking and inflammatory cell simultaneously.
Fig. 2 is that conduit of the present invention amplifies 300 times microphotograph.Can clearly observe aperture on the nerve trachea tube wall of the present invention by this photo.
Absorptive nervous catheter of the present invention is a kind of natural, biodegradation in vivo, the good neurologic defect repair materials that has no side effect.Absorptive nervous catheter can satisfy the condition of operation and each key element that implants fully.Because this nerve trachea has better elastic intensity, guarantee the unimpeded of neural chemotactic regeneration passage.This nerve trachea specific surface has many apertures less than 1 μ m simultaneously, for the neuranagenesis passage has been created good microenvironment.
Further specify the books invention below by embodiment.
Embodiment
1. hot strength method of testing
Use American I nstron universal testing machine carry out this test.Get the long nerve trachea sample of 20mm, clamp the conduit two ends with air pressure, the length of 10mm is stayed in the centre, with the extremely fracture of speed stretching conduit of 1mm/min.The record tensile strength at break point.
2. elastic extension method of testing
Test as mentioned above, the distance D (mm) between when fracture record two clips, calculate the transcatheter elastic extension of fullness of vitality with following formula:
Embodiment 1
Add 100ml 1% lactic acid aqueous solution in the 8g chitosan (deacetylation is greater than 90%, and viscosity is 500Mpas, available from Norway Primex company), abundant stirring and dissolving obtains the lactic acid solution of chitosan.Filter this solution and vacuum removal of air bubbles with 200 eye mesh screens, the lactic acid that obtains chitosan is coated with feed liquid.
With a diameter is that the glass mold rod of the 2mm motor of packing into makes it at the uniform velocity to horizontally rotate with the rotating speed of 35rpm/min, the chitosan lactic acid of preparing previously is coated with on the mould rod surface that feed liquid is coated at the uniform velocity rotation equably, then with infrared heating method at 60 degrees centigrade of following heat dryings.Repeat described coating-drying steps 5 times, then will be molded over nerve trachea on the mould rod and place vacuum desiccator drying at room temperature 3.5 hours under 740mmHg vacuum.
Above-mentioned nerve trachea through intensive drying is soaked the demoulding in 1 hour in 0.2N NaOH solution.
Nerve trachea after the demoulding is washed with water to neutrality, deposit in the distilled water.Sealing is preserved behind sterilization under 120 celsius temperatures.
Measure the performance of nerve trachea with said method, the nerve trachea pipe thickness is that 180 microns, internal diameter are that 2mm, hot strength are that 5N, elastic extension are 50% as a result, and microphotograph shows that its surface has the irregular aperture less than 1 μ m.
Embodiment 2
Add 100ml 2% lactic acid aqueous solution in the 10g chitosan (deacetylation is greater than 90%, and viscosity is 500Mpas, available from Norway Primex company), abundant stirring and dissolving obtains the lactic acid solution of chitosan.Filter this solution and vacuum removal of air bubbles with 200 eye mesh screens, the lactic acid that obtains chitosan is coated with feed liquid.
With a diameter is that the glass mold rod of the 1.5mm motor of packing into makes it at the uniform velocity to horizontally rotate with the rotating speed of 38rpm/min, the chitosan lactic acid of preparing previously is coated with on the mould rod surface that feed liquid is coated at the uniform velocity rotation equably, then with infrared heating method at 60 degrees centigrade of following heat dryings.Repeat described coating-drying steps 5 times, then will be molded over nerve trachea on the mould rod and place vacuum desiccator drying at room temperature 3.5 hours under 740mmHg vacuum.
Above-mentioned nerve trachea through intensive drying is soaked the demoulding in 1.5 hours in 0.5N NaOH solution.
Nerve trachea after the demoulding is washed with water to neutrality, deposit in the distilled water.Sealing is preserved behind sterilization under 120 celsius temperatures.
Measure the performance of nerve trachea with said method, the nerve trachea pipe thickness is that 200 microns, internal diameter are that 1.5mm, hot strength are that 6N, elastic extension are 60% as a result, and microphotograph shows that its surface has the irregular aperture less than 1 μ m.
Embodiment 3
Add 100ml 3% lactic acid aqueous solution in the 12g chitosan (deacetylation is greater than 90%, and viscosity is 500Mpas, available from Norway Primex company), abundant stirring and dissolving obtains the lactic acid solution of chitosan.Filter this solution and vacuum removal of air bubbles with 200 eye mesh screens, the lactic acid that obtains chitosan is coated with feed liquid.
With a diameter is that the glass mold rod of the 4mm motor of packing into makes it at the uniform velocity to horizontally rotate with the rotating speed of 40rpm/min, the chitosan lactic acid of preparing previously is coated with on the mould rod surface that feed liquid is coated at the uniform velocity rotation equably, then with infrared heating method at 60 degrees centigrade of following heat dryings.Repeat described coating-drying steps 5 times, then will be molded over nerve trachea on the mould rod and place vacuum desiccator drying at room temperature 3.5 hours under 740mmHg vacuum.
Above-mentioned nerve trachea through intensive drying is soaked the demoulding in 1 hour in 2N NaOH solution.
Nerve trachea after the demoulding is washed with water to neutrality, deposit in the distilled water.Sealing is preserved behind sterilization under 120 celsius temperatures.
Measure the performance of nerve trachea with said method, the nerve trachea pipe thickness is that 280 microns, internal diameter are that 4mm, hot strength are that 7N, elastic extension are 70% as a result, and microphotograph shows that its surface has the irregular aperture less than 1 μ m.
Embodiment 4
As manufacturing nerve trachea as described in the embodiment 1,, the chitosan lactic acid solution use the natural drying at room temperature method to carry out drying but applying the back.
Measure the performance of nerve trachea with said method, the nerve trachea pipe thickness is that 180 microns, internal diameter are that 2mm, hot strength are that 5N, elastic extension are 50% as a result, and microphotograph shows that its surface has the irregular aperture less than 1 μ m.
Embodiment 5
Add 100ml 2% lactic acid aqueous solution in the 11g chitosan (deacetylation is greater than 90%, and viscosity is 500Mpas, available from Norway Primex company), abundant stirring and dissolving obtains the lactic acid solution of chitosan.Filter this solution and vacuum removal of air bubbles with 200 eye mesh screens, the lactic acid that obtains chitosan is coated with feed liquid.
With a diameter is that the glass mold rod of the 5mm motor of packing into makes it at the uniform velocity to horizontally rotate with the rotating speed of 40rpm/min, the chitosan lactic acid of preparing previously is coated with on the mould rod surface that feed liquid is coated at the uniform velocity rotation equably, then with infrared heating method at 60 degrees centigrade of following heat dryings.Repeat described coating-drying steps 5 times, then will be molded over nerve trachea on the mould rod and place vacuum desiccator drying at room temperature 3.5 hours under 740mmHg vacuum.
Above-mentioned nerve trachea through intensive drying is soaked the demoulding in 1.2 hours in 1N NaOH solution.
Measure the performance of nerve trachea with said method, the nerve trachea pipe thickness is that 300 microns, internal diameter are that 5mm, hot strength are that 5.8N, elastic extension are 59% as a result, and microphotograph shows that its surface has the irregular aperture less than 1 μ m.
Embodiment 5
Get 10 of male SD rats (contrasting 10), sciatic nerve is excised the long nerve segment of 5mm, form artificial neurologic defect model.Sew up bridging with the absorptive nervous catheter (diameter 1.5mm, long 10mm) that embodiment 2 makes at the two ends of damaged nerve.Taking out the neural section of repairing of bridge joint after three months observes: the regenerating nerve growth is normal, even thickness, and the impassivity tumor generates.
Through microscopic examination: it is intensive that regenerating nerve is repaired section regeneration aixs cylinder, and the myelin that has the regeneration Schwann cell to form around the aixs cylinder holds.
Through histological observation: the absorptive nervous catheter rough surface, and exist many cracked stricture of vaginas, surface to see to have a large amount of phagocyte to exist.
Through electric physiological detection: nerve conduction velocity behind the absorptive nervous catheter repair deficiency nerve and autologous nerve reparation group do not have significant difference.Through the triceps surae experiment of weighing, absorptive nervous catheter test group and autologous nerve reparation group muscle weight in wet base also differ and are as good as.
Through biological cell toxicity and Implantation Test: confirm no cytotoxicity and toxic and side effects.
Show that from above zoopery result absorptive nervous catheter is the ideal material that neurologic defect is repaired.
Absorptive nervous catheter of the present invention has advantages such as easy preparation, yield rate height, preparation cost be low, and absorptive nervous catheter of the present invention is a flexible pipe, but long period of soaking is indeformable in water, can avoid nerve trachea to enter behind the human body like this and absorb moisture and produce distortion, it has certain hot strength, satisfies operation stitching and neural tensile requirement so fully, and it has certain elastic strength, it is unimpeded to guarantee that neural chemotactic passage obtains, and avoids subsiding and passage is stopped up.In addition, nerve trachea of the present invention surface has many apertures less than 1 μ m, can satisfy required microenvironment in the neural chemotactic process.
Show according to animal experimental data, do in the peripheral nerve defection repairing test confirming again piglets on one's body, absorptive nervous catheter just had obvious biodegradation effect through 3-4 month.
Claims (9)
1. the preparation method of an absorptive nervous catheter, it comprises the steps:
A) provide the solution of chitosan in lactic acid, this solution contains 80-120 weight portion chitosan and 10-30 weight portion lactic acid;
B) described solution evenly is coated on the mould rod, and heating makes it dry, the temperature of heating is lower than 70 ℃;
C) repeating step b),, obtain the nerve trachea of molding until reaching required coating layer thickness;
D) product that obtains being dipped to conduit in the NaOH of 0.2-2N solution can be from the demoulding on the mould rod.
2. the method for claim 1 is characterized in that it also comprises with the lactic acid solution of 200 purpose screen filtration chitosans and the step of removing bubble before step b).
3. method as claimed in claim 1 or 2 is characterized in that it also comprises the step of vacuum drying product before step d).
4. method as claimed in claim 1 or 2 is characterized in that the heat drying temperature is lower than 60 ℃.
5. method as claimed in claim 1 or 2 is characterized in that in the soaking with sodium hydroxide time be 1-1.5 hour.
6. method as claimed in claim 1 or 2 is characterized in that described mould rod is that rotating speed with 30-40rpm/min at the uniform velocity horizontally rotates.
7. absorptive nervous catheter that makes with each described method among the claim 1-6, the hot strength of this nerve trachea is that 5-7N, elastic extension are 50-70%.
8. absorptive nervous catheter as claimed in claim 7 is characterized in that its hot strength 5-6N, and elastic extension is 50-60%, and described nerve trachea pipe thickness is the 150-300 micron.
9. as claim 7 or 8 described absorptive nervous catheters, it is characterized in that described catheter surface has many diameters less than 1 micron radial direction through hole, the internal diameter of described absorptive nervous catheter is 1.5-5mm.
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| CNB2004100671835A CN100539965C (en) | 2004-10-15 | 2004-10-15 | Absorptive nervous catheter and manufacture method thereof |
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| CNB2004100671835A CN100539965C (en) | 2004-10-15 | 2004-10-15 | Absorptive nervous catheter and manufacture method thereof |
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| CN100539965C true CN100539965C (en) | 2009-09-16 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108992714A (en) * | 2018-08-15 | 2018-12-14 | 费宇奇 | A kind of preparation method of hydrophilic medical conduit |
| CN110448727B (en) * | 2019-09-17 | 2021-10-19 | 南通大学 | Adhesive hydrogel material, suture-free artificial nerve conduit and preparation method thereof |
| CN115591016B (en) * | 2022-11-08 | 2023-12-19 | 南通大学 | Nerve graft with orientation micro-channel and preparation method thereof |
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2004
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Non-Patent Citations (2)
| Title |
|---|
| 不同通透性壳聚糖生物膜复合导管修复周围神经缺损的实验研究. 李青峰，徐靖宏，罗敏，干季良.上海医学，第23卷第7期. 2000 |
| 不同通透性壳聚糖生物膜复合导管修复周围神经缺损的实验研究. 李青峰，徐靖宏，罗敏，干季良.上海医学，第23卷第7期. 2000 * |
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