CN100496619C - Biological-degradable chitosan porous hemostasis material and its preparing method - Google Patents
Biological-degradable chitosan porous hemostasis material and its preparing method Download PDFInfo
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Abstract
The invention supplies a biodegradable nanometer channel multi orifice stanching material and manufacturing method which uses chitosan as raw material. It includes orifice making, forming, orifice making agent removing. The multi orifice structure can be gained by adding orifice making agent in preparation, removing it in forming, which emulsifies to form latex, solidifies to form hydrogel, removes the agent by alcohol or ketone solvent, dries the hydrogel, or processes cross linking for the formaldehyde, glutaraldehyde, solidifies chitosan aqueous solution to form hydrogel, removes the agent by water, dries the hydrogel. This material can fast adsorb the moisture in the blood to stanch.
Description
Technical field
The present invention relates to a kind of porous hemostasis with material and preparation method thereof, be in particular a kind of biodegradable chitosan porous hemostasis material and preparation method thereof.
Background technology
Hemostasis is the important step of various operations and war wound, emergency care of trauma, and present hemostatic material, haemostatic medicament are by thromboembolism, shrink small artery and blood capillary; Strengthen platelet function, quicken, strengthen the blood coagulation process; Suppress the clot dissolution process; Or produce anastalsis by calcination, compressing, stitching blood vessel.People find to have the material of loose structure usually with good hemostatic function in long-term production, practical experience of life, ancestors as us stop blooding with incense ashes very early, the resident of coastal area pounce commonly used stops blooding, and a lot of regional powder that adopts bamboo carbon to wear in China rural area replaces the domestic animal hemostasis at present.The hemostatic function that studies show that these materials is all relevant with their loose structure, when acting on wound, this class loose structure can utilize the distinctive capillarity of liquid, draw the moisture in the wound blood rapidly, thereby the blood coagulation substance in the blood is assembled rapidly, and condense in wound surface, and stop up disruptive blood vessel, reach the hemostatic purpose.U.S. Pat 6,060,461 has described a kind of granular materials with microcellular structure is used for quick-acting haemostatic powder, and its hemostatic function is same because porous structure, its haemostatic effect highly significant also has good haemostatic effect to the massive hemorrhage symptom that causes owing to arteriorrhexis.But this patent is not specifically related to prepare the material of this class microporous particles, and except microporous particles, the porous material of other type is as the application of hemostatic material, as porous fibre, mandruka etc., and the preparation method of this class porous hemostasis material, this material can't be degraded simultaneously, might cause harmful effect to human body.And in biodegradable natural macromolecular material, chitosan is the amino macromolecule polysaccharide that a class is extracted from Crustaceans such as shrimp, Eriocheir sinensis, its source is abundant, has excellent biological compatibility, simultaneously owing to have electropositive characteristics, can with the rapid combination of electronegative erythrocyte, form block tamper, bleed thereby stop, so chitosan also is widely used in preparing tourniquet bandage.In view of the two haemostatic effect, how utilizing chitosan to make biodegradable porous hemostasis material is the problem always explored of people in recent years.
Summary of the invention
Purpose of the present invention is exactly to provide a kind of hemostatic function and distinctive hemostatic function of chitosan material with loose structure to combine for the above-mentioned deficiency that solves prior art, by Preparation of Chitosan, the biodegradable chitosan porous hemostasis material of biodegradable, as to have loose structure quick-acting haemostatic powder.
Another object of the present invention provides the preparation method of above-mentioned biodegradable chitosan porous hemostasis material.
Purpose of the present invention can realize by following technical solution: the biodegradable chitosan porous hemostasis material, form with biodegradable natural macromolecular Preparation of Chitosan, it is characterized in that: the raw material deacetylation of chitosan is generally between 80%～99%, mean molecule quantity is 10,000～10
6Between.Described hemostatic material surface and inner nanometer, the micron order through hole of forming, the size in described its aperture is between 10 nanometers～30 micron, and porosity accounts for the 20%-80% of whole material, preferred 30%-70%.Described hemostatic material is porous microsphere form, porous fibre form, mandruka form, or the compound system of several types.
The preparation method of biodegradable chitosan porous hemostasis material of the present invention, operations such as it comprises perforating agent drilling, forming materials, remove perforating agent, lyophilization, ozone-plasma surface oxidation, it is characterized in that: the loose structure of described hemostatic material is by adding perforating agent in the preparation process of hemostatic material, removes perforating agent and obtain in the hemostatic material forming process; Perforating agent is the oil-soluble organic reagent, as vegetable oil, petroleum ether, decahydronaphthalene, toluene etc., containing 5-20% water soluble emulsifier (weight ratio) as Tween 80, add the oil-soluble organic reagent (weight ratio) of 5%-40% in the aqueous acetic acid of the chitosan of Triton X-100 etc. as perforating agent, form emulsion by emulsive method, crosslinked, solidify and make emulsion form hydrogel, with other and the molten alcohol of water, ketone solvent such as ethanol etc., the organic perforating agent of flush away oil-soluble, dry above-mentioned hydrogel, can obtain loose structure: or adopt following Biodegradable natural macromolecular material or polymeric type material as the water soluble polymer perforating agent: collagen protein, glucosan, sodium alginate, polyvinyl alcohol, Polyethylene Glycol water-soluble high-molecular material perforating agent, be dissolved in the aqueous acetic acid jointly with chitosan material, concentration is 5%-40% (weight ratio), and pH value is 3-6.5; By formaldehyde, crosslinked, the curing chitosan aqueous solution of glutaraldehyde cross-linking, form hydrogel, wash the soluble macromolecular perforating agent that anhydrates with water, dry above-mentioned hydrogel can obtain loose structure.Crosslinked, the curing of cross-linking agent is mainly adopted in the formation of biodegradable natural macromolecular aquagel.Chitosan is dissolved in the aqueous acetic acid, with formaldehyde, glutaraldehyde cross-linking.Among the present invention, the cryodesiccated method of dry main employing of biodegradable natural macromolecular aquagel finally obtains porous hemostasis material.Porous microsphere, porous fibre, mandruka adopt different forming methods to be prepared respectively.
The oil-soluble perforating agent adopts vegetable oil, petroleum ether, decahydronaphthalene, toluene etc., in the aqueous acetic acid of the chitosan that contains the water soluble emulsifier of 5-20% (weight ratio), add 5%-40% oil-soluble reagent (weight ratio) as perforating agent, carry out emulsifying and form emulsion, crosslinked, curing makes emulsion form hydrogel, with other and molten alcohol, the ketone solvent of water, as ethanol, acetone etc., the oil-soluble perforating agent in the flush away hydrogel, dry above-mentioned hydrogel can obtain loose structure.Chitosan is dissolved in the aqueous acetic acid, with formaldehyde, glutaraldehyde cross-linking agent.
The consumption of cross-linking agent is unrestricted, generally is that the acetic acid amount of substance is suitable.
The preparation of chitosan porous microsphere is to be scattered in oil-soluble organic reagent with above-mentioned emulsion or aqueous solution are anti-phase, in petroleum ether, toluene, decahydronaphthalene, the amount of oil-soluble organic reagent is emulsion or water-soluble liquid measure 2-10 a times, and contain the oil soluble emulsifying agent of 5%-20%, form reversed-phase emulsion.Behind the formaldehyde of the 5%-50% of chitosan mass, the glutaraldehyde cross-linking, form hydrogel, the perforating agent in the flush away hydrogel, dry above-mentioned hydrogel can obtain porous microsphere; Or with above-mentioned emulsion or aqueous solution, be that the high pressure nozzle of 1-100 micron is atomized into the liquid pearl by aperture, and bathe through superheated air bath or nitrogen, remove perforating agent and moisture, obtain porous microsphere; Perhaps, be scattered in the solvent such as ethanol that dissolves each other with water (coagulating bath) the liquid pearl of atomizing, precipitated outlet water gel micro-ball, and further crosslinked, curing, the flush away perforating agent obtains porous microsphere after lyophilization.
The preparation of chitosan multi-porous fiber is not to be dispersed in (emulsifying or dissolving) in the aqueous acetic acid that is dissolved with chitosan material with oil-soluble perforating agent or water solublity perforating agent are non-, obtain emulsion or solution system, behind this emulsion/solution process spinning head spray webbing, the fiber that obtains is bathed through superheated air bath or nitrogen, remove perforating agent and moisture, obtain porous fibre; Perhaps with the fiber dispersion behind the spray webbing in the solvent such as ethanol that dissolve each other with water (coagulating bath), the precipitated outlet water gelatinous fibre, and further crosslinked, solidify, the flush away perforating agent obtains porous fibre after lyophilization.
The preparation of chitosan multi-porous sponge is that oil-soluble perforating agent or water solublity perforating agent are dispersed in the aqueous acetic acid that is dissolved with chitosan, be uniformly dispersed, add formaldehyde, glutaraldehyde cross-linking agent, after rapidly above-mentioned solution being injected specific mould formation gel then, the demoulding, the flush away perforating agent obtains mandruka after lyophilization.
The cryodesiccated method of dry main employing of biodegradable natural macromolecular aquagel finally obtains porous hemostasis material.
Purpose of the present invention also can further realize by following technology solution:
Among the present invention, crosslinked, the curing of cross-linking agent is mainly adopted in the formation of biodegradable natural macromolecular aquagel.Chitosan is dissolved in the aqueous acetic acid, and is crosslinked with formaldehyde, glutaraldehyde etc.Among the present invention, the cryodesiccated method of dry main employing of biodegradable natural macromolecular aquagel finally obtains porous hemostasis material.
Among the present invention in order further to increase the water absorbing properties of biodegradable natural macromolecular hemostatic material, adopt plasma etching instrument or UV ozone cleaner, the ozone-plasma that is produced with the ozone-plasma oxidation technology is carried out shallow degree oxidation processes to the surface of material and nanometer, a micron channel surface, the hydrophilicity of reinforcing material, this method for oxidation can be avoided the uncontrollability of traditional chemical method for oxidation and pollution and the destruction that may cause material, and can play the effect of sterilization, sterilization.
The invention has the advantages that the loose structure that has a large amount of perforations at material surface and material internal, form the passage of micron pore size and nano aperture, make material have big specific surface area, the water absorbing properties of reinforcing material, because the distinctive capillarity of liquid, moisture in the blood is by these microns passage, nanochannel can be by fast Absorption, and the erythrocyte in the blood, blood coagulation substances such as platelet since size greater than micron, the aperture of nanochannel, then can not pass through these passages, will enrichment, pile up, condense in the wound, stop up the blood vessel that firmly breaks, reach the purpose of quick-acting haemostatic powder.Simultaneously because chitosan has electropositive characteristics, can with the rapid combination of electronegative erythrocyte, promote to form block tamper, thus the further anastalsis of reinforcement material.
Hemostatic material among the present invention can be respectively porous microsphere, porous fibre, porous block form of sponge, or several types is composited.
Among the present invention, the chitosan that is used for preparing porous hemostasis material is the amino macromolecule polysaccharide that a class is extracted from Crustaceans such as shrimp, Eriocheir sinensiss, its feature is that occurring in nature source is abundant, good hydrophilic property, good biocompatibility, biological activity excellence, biological degradability are good, also have antibiotic, antiinflammatory, analgesia, hemostasis and the growth of promotion when injected organism tissue, promote functions such as wound healing, be fit to direct adjuvant as hemostatic material or hemostatic material.The deacetylation of used chitosan material is generally between 80%-95% among the present invention, and viscosity-average molecular weight is generally 10,000-10
6Between.
Porous hemostasis material among the present invention, the loose structure that has a large amount of perforations at material surface and material internal, form the passage of micron pore size and nano aperture, make material have big specific surface area, the water absorbing properties of reinforcing material, because the distinctive capillarity of liquid, moisture in the blood is by these microns passage, nanochannel can be by fast Absorption, and the erythrocyte in the blood, blood coagulation substances such as platelet since size greater than micron, the aperture of nanochannel, then can not pass through these passages, will enrichment, pile up, condense in the wound, stop up the blood vessel that firmly breaks, reach the purpose of quick-acting haemostatic powder.Simultaneously because chitosan has electropositive characteristics, can with the rapid combination of electronegative erythrocyte, promote to form block tamper, thus the further anastalsis of reinforcement material.The aperture of loose structure is generally between 10 nanometers-30 micron, the porosity of porous material among the present invention (porosity is the volume of loose structure in the hemostatic material and the ratio of the volume of hemostatic material), generally 20% ~ 80%, preferred 30% ~ 70%, low excessively porosity can reduce the haemostatic effect of material, too high porosity then can reduce the mechanical strength of material.The loose structure of porous material and aperture obtain by electron microscope observation among the present invention, and porosity adopts mercury injection method to measure by mercury injection apparatus.
The loose structure of hemostatic material is by adding perforating agent in the preparation process of hemostatic material among the present invention, removes perforating agent and obtain in the hemostatic material forming process.Perforating agent can be the oil-soluble organic reagent, as vegetable oil, petroleum ether, decahydronaphthalene, toluene etc., in the aqueous acetic acid of the chitosan that contains 5-20% water soluble emulsifier (weight ratio), add the oil-soluble organic reagent (weight ratio) of 5%-40% as perforating agent, form emulsion by emulsive method, crosslinked, curing makes emulsion form hydrogel, with other and molten alcohol, ketone solvent such as the ethanol etc. of water, the organic perforating agent of flush away oil-soluble, dry above-mentioned hydrogel can obtain loose structure; Perforating agent also can be water-soluble high-molecular material, as other Biodegradable natural macromolecular material collagen protein, glucosan, sodium alginate etc. or polymeric type material, polyvinyl alcohol, Polyethylene Glycol etc., be dissolved in jointly in the aqueous acetic acid with chitosan material, concentration is 5%-40% (weight ratio), by crosslinked, curing chitosan aqueous solution, form hydrogel, wash the soluble macromolecular perforating agent that anhydrates with water, dry above-mentioned hydrogel can obtain loose structure.
Among the present invention, crosslinked, the curing of cross-linking agent is mainly adopted in the formation of biodegradable natural macromolecular aquagel.Chitosan is dissolved in the aqueous acetic acid, and concentration is 1-10% (weight ratio), and with formaldehyde, glutaraldehyde cross-linking, the consumption of cross-linking agent is chitosan amount 5%-50% (weight ratio).Among the present invention, the cryodesiccated method of dry main employing of biodegradable natural macromolecular aquagel finally obtains porous hemostasis material.
Biodegradable natural macromole porous hemostasis material among the present invention can be porous microsphere shape, porous fibre shape, mandruka shape, or the compound system of several types.Porous microsphere, porous fibre, mandruka adopt different manufacturing process to be prepared respectively.Generally between the 1-1000 micron, preferable particle size is at the microsphere of 5-500 micron for the particle diameter of porous microsphere among the present invention; The diameter of the porous fibre among the present invention generally between the 1-200 micron, the fiber between the preferred diameter 5-100 micron; The size of the mandruka among the present invention can obtain by the size of regulating grinding tool according to actual needs.Porous microsphere among the present invention can adopt water/oily reversed-phase emulsion system to be prepared, at first be not dispersed in (emulsifying or dissolving) in the aqueous acetic acid that is dissolved with chitosan material with oil-soluble perforating agent or water solublity perforating agent are non-, then with above-mentioned emulsion or solution at oil-soluble organic solvent such as petroleum ether, decahydronaphthalene, rp-emulsification in the toluene, the amount of oil-soluble organic reagent is emulsion or water-soluble liquid measure 2-10 a times, and contain the oil soluble emulsifying agent (weight ratio) of 5%-20%, obtaining water/oil body is reversed-phase emulsion, formaldehyde or glutaraldehyde cross-linking, solidify the back and obtain hydrogel microsphere, ethanol flush away oil-soluble perforating agent, or water is removed the water solublity perforating agent, and lyophilization, obtain porous microsphere.Porous microsphere among the present invention also can adopt and be atomized into the liquid microsphere earlier, solidify, crosslinked method, at first perforating agent is dispersed in the aqueous solution that is dissolved with chitosan material, by aperture is that 1-100 micron high pressure nozzle is atomized into the liquid pearl, and through superheated air bath or nitrogen bath, remove perforating agent and moisture, obtain porous microsphere; Perhaps with the liquid pearl of atomizing, be scattered in the solvent such as ethanol that dissolves each other with water (coagulating bath), precipitated outlet water gel micro-ball, and further crosslinked, curing obtain porous microsphere after lyophilization.The preparation of porous fibre is that oil-soluble or water solublity perforating agent are dispersed in emulsifying or dissolving in the aqueous acetic acid that is dissolved with chitosan respectively among the present invention, obtain emulsion or solution system, behind this emulsion/solution process spinning head spray webbing, the fiber that obtains is bathed through superheated air bath or nitrogen, remove perforating agent and moisture, obtain porous fibre; Perhaps with the fiber dispersion behind the spray webbing in the solvent such as ethanol that dissolve each other with water (coagulating bath), the precipitated outlet water gelatinous fibre, and further crosslinked, solidify, the flush away perforating agent obtains porous fibre after lyophilization.The preparation of mandruka is that perforating agent is dispersed in the aqueous acetic acid that is dissolved with chitosan among the present invention, is uniformly dispersed, and adds cross-linking agent, rapidly above-mentioned solution is injected specific mould then, behind the formation gel, the demoulding, the flush away perforating agent obtains mandruka after lyophilization.
Used emulsifying agent is water miscible emulsifying agent among the present invention, as Tween 80, Triton X-100; And oil soluble emulsifying agent, as Span 85, Arlacel 83 etc.The factors such as consumption of the concentration of the molecular weight of chitosan, deacetylation and aqueous solution, perforating agent kind, consumption, emulsifying agent kind, consumption, cross-linking agent all can finally influence the haemostatic effect of porous material among the present invention.
Among the present invention in order further to increase the water absorbing properties of biodegradable chitosan porous hemostasis material, adopt ozone plasma oxidation technology that plasma etching instrument or UV ozone cleaning appts produce that the surface of material and nanometer, a micron channel surface are carried out shallow degree oxidation processes, the hydrophilicity of reinforcing material, this method for oxidation can be avoided the uncontrollability of traditional chemical method for oxidation and pollution and the destruction that may cause material, and can play the effect of sterilization, sterilization.
When the biodegradable chitosan porous hemostasis material among the present invention is applied to stop blooding, can directly overlays the bleeding part or after it covers the bleeding part, adopt the mode of pushing to be fixed in the bleeding part.Chitosan porous microsphere can directly spray on the surface, bleeding part, or covers thereon to push behind the gauze and stop blooding.Chitosan multi-porous fiber acts on the bleeding part after can being prepared into styptic cotton.Chitosan multi-porous sponge can directly act on the bleeding part.Also can different materials be compound one reacts on hemorrhage position again with porous microsphere, porous fibre, mandruka etc. in this name.
Description of drawings
Fig. 1 and Fig. 2 are the SEM photo of chitosan porous hemostasis material
The specific embodiment
1. the preparation of chitosan porous microsphere
The 2g deacetylation is 90%, and viscosity-average molecular weight is that 500,000 chitosan is dissolved in 98g, 3% the aqueous acetic acid, adds 5g Tween 80, adds 20g plant soybean oil then, vigorous stirring, and emulsifying is even.The 1000ml that above-mentioned emulsion is added dropwise to vigorous stirring contains in the normal hexane of 60g Span 85, emulsifying 1 hour, add 2ml, 20% glutaraldehyde water solution, continue to stir 1 hour, filter the back with 50% ethanol water flush away soybean oil and emulsifying agent, obtain chitosan porous microsphere after the lyophilization.
2. the preparation of chitosan multi-porous fiber
The 3g deacetylation is 90%, viscosity-average molecular weight is 500,000 chitosan is dissolved in 97g, 5% the aqueous acetic acid, add 5g Triton x-100 and 10ml normal hexane, vigorous stirring, emulsifying, above-mentioned emulsion is through the spinning head spray webbing of spinning-drawing machine, and the strand of ejection was by coagulating bath (ethanol-aqueous solution of 2% glutaraldehyde) curing, crosslinked 0.5 hour, the fiber that obtains with ethanol flush away normal hexane and and emulsifying agent, obtain chitosan multi-porous fiber through lyophilization.
3. the preparation of chitosan multi-porous sponge
The 5g deacetylation is 90%, viscosity-average molecular weight is that 100,000 chitosan is dissolved in 95g, 5% the aqueous acetic acid, and adding the 10g molecular weight is 5,000 Polyethylene Glycol, stir, Polyethylene Glycol is dispersed in the chitosan aqueous solution, add 2ml, 20% formalin, rapidly above-mentioned dispersion liquid be injected in certain mould, solidify, crosslinked 0.5 hour, after the system for the treatment of formed hydrogel, water flush away Polyethylene Glycol obtained chitosan multi-porous sponge after the lyophilization.
4. the surface oxidation treatment of chitosan porous hemostasis material
Above-mentioned chitosan porous hemostasis material is placed the plasma etching instrument, with ozone plasma to material processed 3-5 minute.
5. hemostasis embodiment
A. the hemostasis of the little angiorrbagia of Mus afterbody
The Wistar rat, ♂, body weight 280 ± 30g is provided by Military Medical Science Institute's Experimental Animal Center.Rat pentobarbital sodium 50mg/kg ip anesthesia, it is fixing to lie on the back, tracheal intubation, rat tails is sterilized with disinfectant solution, afterbody is sawed-off at the most advanced and sophisticated 5cm of afterbody place with sharp blade, immediately the following pad of residual afterbody section one gauze of weighing in advance, and quantitative chitosan porous microsphere is sprinkling upon rapidly on the afterbody section, write down the bleeding time simultaneously,, calculate blood loss with the weight of weight method weighing gauze.Experimental technique sees list of references for details: Kathy L.Ryan, et al.Efficacy of FDA-approved hemostatic drugs to improve survival and reducebleeding in rat models of uncontrolled hemorrhage.Resuscitation (the rat haemostatic medicament of FDA approval recovers the survival model) 2006; 70:133-144. 2. Stephen W.Rothwell et al.Addition of a propyl gallate-based procoagulant to a fibrin bandage improveshemostatic performance in a seine arterial bleeding model (vein hemostasis model) .Thromvosis Research 2003:108:335-340.
Table 1 hemostatic material is to the anastalsis of the little angiorrbagia of rat tails
| The hemostatic material numbering | Blood loss (g) | Bleeding time (min) |
| Common gauze | 2.77±1.21 | 7.26±3.45 |
| The chitosan gauze | 2.01±0.98 | 6.65±3.01 |
| Chitosan porous microsphere (50 microns of mean diameters, porosity 80%) | 0.28±0.06 | 0.88±0.23 |
Chitosan multi-porous hemostasis microsphere is compared with chitosan gauze matched group with common gauze, and the anastalsis of generation is rapid-action, haemostatic effect is definite, can significantly reduce the afterbody blood loss, obviously shortens the bleeding time.Can be used for the hemorrhage hemostasis of tiny blood vessels clinically, and the hemostasis of some traumatic hemorrhage.
B. the hemorrhage hemostasis of rabbit liver tiny blood vessels permeability
New Zealand white rabbit, ♂, body weight 2.8 ± 0.3kg is provided by Military Medical Science Institute's Experimental Animal Center.Rat pentobarbital sodium 45mg/kg ip anesthesia, it is fixing to lie on the back, tracheal intubation, the rabbit right upper quadrant of the abdomen is shaved hair, use iodine disinfection, right upper quadrant of the abdomen is opened abdomen, exposes liver, cut the circular wound surface of a diameter 1.5cm at the frontal lobe of liver, make its oozing of blood, immediately quantitative styptic powder is sprinkling upon on the wound surface, and cover with the gauze of weighing in advance, the record bleeding stopping period is with the hemorrhage blood loss of weight method weighing liver tiny blood vessels permeability.Experimental technique sees list of references for details: Kathy lRyan, et al.Efficacy of FDA-approved hemostatic drugs to improve survivaland reduce bleeding in rat models of uncontrolled hemorrhage.Resuscitation2006:70:133-144.
Table 2 hemostatic material is to the hemorrhage anastalsis of rabbit liver tiny blood vessels permeability
| The hemostatic material numbering | Blood loss (g) | Bleeding time (mi |
| Common gauze | 16.25±3.23 | 14.11±5.26 |
| The chitosan gauze | 15.733.98 | 13.43±6.22 |
| Chitosan porous microsphere (50 microns of mean diameters, porosity 80%) | 3.89±1.96 | 1.06±0.33 |
The result shows, chitosan porous microsphere compares with matched group that the anastalsis of generation is rapid-action, haemostatic effect is definite, can significantly reduce the hemorrhage blood loss of liver tiny blood vessels permeability, obviously shortens the bleeding time.Can be used for the hemorrhage hemostasis of tiny blood vessels clinically, the hemorrhage hemostasis of especially various internal organs permeabilitys.
C. the hemostasis of rabbit femoral vein angiorrbagia
New Zealand white rabbit, ♂, body weight 2.8 ± 0.3kg is provided by Military Medical Science Institute's Experimental Animal Center.Rat pentobarbital sodium 45mg/kg ip anesthesia, it is fixing to lie on the back, tracheal intubation, rabbit right side groin is shaved hair, use iodine disinfection, cut off skin, separate subcutaneous tissue, expose femoral vein, femoral vein is cut off fully, it is bled, immediately quantitative chitosan porous microsphere is sprinkling upon on the wound surface, and covers, and place the counterweight of a 50g with the gauze of weighing in advance, the record bleeding stopping period is with the blood loss of weight method weighing rabbit femoral vein angiorrbagia.Experimental technique sees list of references for details: the same.
Table 3 hemostatic material is to the anastalsis of rabbit femoral vein angiorrbagia
| The hemostatic material numbering | Blood loss (g) | Bleeding time (min) |
| Common gauze | 35.12±6.02 | 11.16±3.32 |
| The chitosan gauze | 33.57±5.22 | 10.253.01 |
| Chitosan porous microsphere (50 microns of mean diameters, porosity 80%) | 6.35±3.36** | 1.51±0.58** |
Table 3 is the result show, chitosan porous microsphere compares with matched group that the anastalsis of generation is rapid-action, haemostatic effect is definite, can significantly reduce rabbit femoral vein angiorrbagia blood loss, obviously shortens the bleeding time.Can be used for the hemorrhage hemostasis of vein blood vessel clinically.
D. the rabbit femoral artery blood vessel hemostasis of bleeding
New Zealand white rabbit, ♂, body weight 2.8 ± 0.3kg is provided by Military Medical Science Institute's Experimental Animal Center.Rat pentobarbital sodium 45mg/kg ip anesthesia, it is fixing to lie on the back, tracheal intubation, rabbit right side groin is shaved hair, use iodine disinfection, cut off skin, separate subcutaneous tissue, separate one section femoral artery, the about 3.5cm of length, clamp with bulldog clamp respectively at two ends, on femoral artery, cut the slotted eye of a 2 * 3mm with the carefulness of ophthalmology iris scissors, take out the bilateral bulldog clamp, it is bled, immediately quantitative chitosan porous microsphere is sprinkling upon on the wound surface, and gauze covering to weigh in advance, and place a 100g counterweight, the record bleeding stopping period is with the blood loss of weight method weighing rabbit femoral artery angiorrbagia.Experimental technique sees list of references for details: the same 3. BijanS.Khei rabadi that reaches, Ph.D., et al.Comparativestudy of the efficacy of the common topical hemostatic agents with fibrinsealant in a rabbit aortic anastomosis model (exempting from the blood vessel hemostasis model) .Journal ofSurgical research 2002:106:99-107.
The anastalsis that table 4 hemostatic material is bled to rabbit femoral artery blood vessel
| The hemostatic material numbering | Blood loss (g) | Bleeding time (min) |
| Common gauze | 56.55±8.76 | 33.12±8.56 |
| The chitosan gauze | 47.73±7.62 | 29.53±7.03 |
| Chitosan porous microsphere (50 microns of mean diameters, porosity 80%) | 7.12±3.78** | 2.22±0.73** |
The result shows, chitosan porous microsphere compares with matched group that the anastalsis of generation is rapid-action, haemostatic effect is definite, can significantly reduce the blood loss that rabbit femoral artery blood vessel is bled, and obviously shortens the bleeding time.Can be used for the hemostasis that trunk hemorrhage hemostasis, especially war wound, various wound cause massive hemorrhage clinically.
The invention provides a kind of is the nanometer microchannel porous hemostasis material of raw material with the biodegradable chitosan material.Biodegradation hemostatic material involved in the present invention is made of hydrophilic, biodegradable natural macromolecular material chitosan, by certain hole fabrication techniques, surface and inner MCA and the loose structure that connects that form at chitosan material, the distribution in aperture is from 10 nanometers to 10 micron, the form of this kind hemostatic material can be porous microsphere, porous fibre, mandruka, or several types is compound.This kind material is the moisture in the absorbing blood rapidly, makes the hemocyte in the blood condense in wound surface, stop up the blood vessel that firmly breaks, and reaches the quick-acting haemostatic powder purpose, and what be specially adapted to that hemorrhage, the dynamic and static angiorrhexis of large tracts of land permeability causes is hemorrhage.
Claims (10)
1. the biodegradable chitosan porous hemostasis material forms with biodegradable natural macromolecular Preparation of Chitosan, it is characterized in that: chitosan raw material deacetylation is between 80%～95%, and mean molecule quantity is 10,000～10
6Between; Described hemostatic material surface and inner nanometer, the micron order through hole of forming, the size in described its aperture is between 10 nanometers～30 micron, and porosity accounts for the 20%-80% of whole material.
2. biodegradable chitosan porous hemostasis material according to claim 1 is characterized in that: described hemostatic material is the compound system of porous microsphere form, porous fibre form, mandruka form or above-mentioned form.
3. the preparation method of biodegradable chitosan porous hemostasis material according to claim 1 and 2, comprise the perforating agent drilling, forming materials, remove the operation of perforating agent, it is characterized in that: the loose structure of described biodegradable chitosan porous hemostasis material is by add perforating agent in the preparation process of hemostatic material, remove perforating agent and obtain in the hemostatic material forming process: perforating agent is the oil-soluble organic reagent: vegetable oil, petroleum ether, decahydronaphthalene or toluene, in the aqueous acetic acid of the chitosan that contains 5-20% water soluble emulsifier (weight ratio), add the oil-soluble organic reagent (weight ratio) of 5%-40% as perforating agent, water soluble emulsifier is Tween 80 or TritonX-100, form emulsion by emulsive method, crosslinked, solidify and make emulsion form hydrogel, with other and the molten alcohol of water, the organic perforating agent of ketone solvent flush away oil-soluble, dry above-mentioned hydrogel can obtain loose structure; Or adopt following Biodegradable natural macromolecular material or polymeric type material as the water soluble polymer perforating agent: with collagen protein, glucosan, sodium alginate, polyvinyl alcohol or Polyethylene Glycol water-soluble high-molecular material as perforating agent, be dissolved in the aqueous acetic acid jointly with chitosan material, concentration is 5%-40% (weight ratio), and pH value is 3-6.5; , curing chitosan aqueous solution crosslinked by formaldehyde or glutaraldehyde cross-linking agent form hydrogel, wash the soluble macromolecular perforating agent that anhydrates with water, and dry above-mentioned hydrogel can obtain the loose structure hemostatic material.
4, the preparation method of biodegradable chitosan porous hemostasis material according to claim 3 is characterized in that adopting ozone that plasma etching instrument or UV ozone cleaner produce or plasma that described hemostatic material surface and nanometer, a micron channel surface are carried out shallow degree oxidation processes.
5, the preparation method of biodegradable chitosan porous hemostasis material according to claim 3 is characterized in that the alcohol, the ketone solvent that adopt water molten, the organic perforating agent of flush away oil-soluble, the washing dissolubility perforating agent that anhydrates; The drying of biodegradable natural macromolecular aquagel adopts cryodesiccated method.
6. the preparation method of biodegradable chitosan porous hemostasis material according to claim 3, the preparation method that it is characterized in that the porous microsphere hemostatic material is: adopt water/fat liquor system to be prepared, at first perforating agent is disperseed in the aqueous acetic acid of chitosan, form emulsion or aqueous solution, then with above-mentioned emulsion/aqueous solution rp-emulsification in oil-soluble organic solvent, obtain oil/water/oil body system, obtain hydrogel microsphere behind crosslinked, the cured matrix material, the flush away perforating agent, and lyophilization, obtain the porous microsphere hemostatic material.
7, the preparation method of biodegradable chitosan porous hemostasis material according to claim 6, the preparation method that it is characterized in that the porous microsphere hemostatic material, described oil-soluble organic solvent is petroleum ether, decahydronaphthalene or toluene, the oil soluble emulsifying agent (weight ratio) that wherein contains 5%-20%, oil soluble emulsifying agent are Span 85 or Arlacel 83.
8. the preparation method of biodegradable chitosan porous hemostasis material according to claim 6, it is characterized in that the porous microsphere preparation method: at first perforating agent is dispersed in the aqueous acetic acid of chitosan, by aperture is that 1-100 micron high pressure nozzle is atomized into the liquid pearl, and through superheated air bath or nitrogen bath, remove perforating agent and moisture, obtain porous microsphere; Perhaps, be scattered in the solvent that dissolves each other with water the liquid pearl of atomizing, the precipitated outlet water gel micro-ball, crosslinked again, curing obtains porous microsphere after lyophilization.
9, the preparation method of biodegradable chitosan porous hemostasis material according to claim 6, the preparation method that it is characterized in that porous fibre is: perforating agent is dispersed in emulsifying or dissolving in the aqueous acetic acid of molten chitosan, obtain the emulsion/solution system, behind emulsion/solution process spinning head spray webbing, the strand that obtains is through coagulating bath, curing, crosslinked obtains removing perforating agent behind the fiber again, obtains porous fibre after lyophilization.
10. the preparation method of biodegradable chitosan porous hemostasis material according to claim 6, the preparation method that it is characterized in that mandruka is: perforating agent is dispersed in the aqueous acetic acid of chitosan, then the solution that disperses perforating agent is injected specific mould, crosslinked, solidify to form gel after, the demoulding, flush away dispersant, and further crosslinked, curing obtain after lyophilization.
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