CN104474575A - Chitosan hemostatic material formed through covalent crosslinking and preparation method thereof - Google Patents
Chitosan hemostatic material formed through covalent crosslinking and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a chitosan hemostatic material formed through covalent crosslinking and a preparation method thereof. The chitosan hemostatic material formed through covalent crosslinking is obtained by chemically crosslinking chitosan by utilizing a crosslinking agent via covalent bonds, wherein the crosslinking agent is polyethylene glycol diglycidyl ether. The preparation method of the chitosan hemostatic material formed through covalent crosslinking comprises the following steps: 1) preparing chitosan into a water solution; 2) adding the crosslinking agent to the chitosan water solution, fully stirring and mixing the materials, then pouring the mixture into a mold, and freeze-drying the product, thus obtaining the chitosan hemostatic material, wherein the crosslinking agent is polyethylene glycol diglycidyl ether. The chitosan hemostatic material and the preparation method have the beneficial effects that chitosan is crosslinked by polyethylene glycol diglycidyl ether under acidic conditions; an ethylene oxide group in polyethylene glycol diglycidyl ether carries out ring-opening reaction with hydroxyl on chitosan under acidic conditions to form the crosslinked product by generating ether bonds; the crosslinking agent used in the method is relatively safe; the preparation process is simple and practicable and is lower in production cost.
Description
Technical field
The present invention relates to chitosan hemostatic material of covalent cross-linking formation and preparation method thereof.
Background technology
The hemorrhage of human body can occur in various situation, such as, and the size wound in surgical operation, arterypuncture (arterial intervention diagnosis and interventional therapy), war wound and daily life.What human body was a large amount of lose blood can cause serious consequence, so that life-threatening.It is the second reason of civilian deaths in daily life that wound non-controlling is lost blood, and is first cause of the death on battlefield.Therefore, the research and development for hemostatic material are the focuses paid close attention to both at home and abroad always.
Up to now, in the process of surgery operative hemorrhage, the hemostatic material used clinically is mainly the derived material of degradable natural polymer, as gelfoam, oxidized cellulose, microfibrillar collagen powder, Fibrin Glue and collagen sponge.But all deficiencies due to them cannot meet widespread demand (Hu Guoying, Gu Hanqing, the new development of hemorrhage Preclinic and clinic applied research clinically; Dialysis and artificial organ [J] 2010 .6: 21 (2): 29-35).
Chitosan, also known as poly-
glucoseamine (1-4)-2-amino-beta--D glucose is a kind ofly extensively present in the linear cationic polysaccharide of natural chitin by obtaining after partially deacetylated.Be widely studied owing to itself being considered to have the advantages such as good biocompatibility, degradability, antibacterial activity and promotion wound healing.After nineteen eighty-three Malette etc. has delivered the result of the hemostatic function of chitosan, scientists has started to attempt adopting chitosan development hemostatic material.In JIUYUE, 2002, U.S. FDA have approved the HemCon hemostasia products produced by HemCon Medical Technologies company of the U.S., and this product was used by US military in Afghan War in 2003.Up to now, U.S. FDA have approved listing such as chitosan class hemostasia products such as HemCon hemostasis bandage, CELOX, Clo-Sur P.A.D etc.
Simultaneously, also the result of study that patent discloses chitosan class hemorrhage is had both at home and abroad, such as, US Patent No. 4532134 relate to the optimization to the condition such as solution concentration and pH value of solution after chitosan material deacetylation, molecular weight, dissolving solvent for use, dissolving, prepare chitose haemostatic, and demonstrate chitose haemostatic by zoopery not only there is good haemostatic effect, also have simultaneously and can suppress fibroplasia, promote the effects such as tissue regeneration.Direct use chitosan comprises for raw material carries out patent prepared by sthptic sponge, Chinese invention patent ZL03153820.7,200810198164.4,201010291789.2 and Chinese invention patent application 02109638.4,200680030822.8,200110115108.5,201110382475.8,201210545888.8,201210033793.8.Wherein, Chinese invention patent 201010291789.2 discloses novel chitosan extracting method, the new technology extracted makes chitosan sthptic sponge by oneself, obtains the hemostatic material that porous easily absorbs after lyophilizing, and proved by zoopery, this hemostatic material has superior anthemorrhagic performance.Studies have found that, the chitosan sponge mechanical strength that direct use chitosan is prepared for raw material is poor, therefore some relevant patents of improving one's methods have been there is successively, such as, Chinese invention patent 200810198164.4 and Chinese invention patent application 200710115108.5,02109638.4,20101048730.8 disclose the correlation technique utilizing other natural polysaccharide materials and chitosan to carry out mixing, preparing sthptic sponge.But, preparing craft is complicated and the hemorrhage humid stability obtained is poor (meeting blood dissolve or become gel), the such as porous sthptic sponge be prepared from for main component with chitosan and gelatin of current most study, easily dissolve in the wound of bleeding profusely, Blood clotting (Wu Bin cannot be played, Sun Yun etc. a kind of sthptic sponge preparation method [P] for adjuvant. Chinese invention patent application 201210545888.8,2012-12-14).
In order to solve the problem, use that cross-linking agent carries out crosslinked to chitosan and technology that is that prepare hemorrhage is developed, such as patent CN9110678.4 discloses and is added in chitin solution by glycerol, then carries out crosslinking curing with formaldehyde, washes away the technology of formaldehyde section encapsulation after freeze forming.It is said, utilize sthptic sponge quality obtained by the method soft have good histocompatibility, nontoxic with human body, non-stimulated to wound surface; It is that raw material uses glutaraldehyde or formaldehyde to carry out the crosslinked method preparing sponge that patent CN03112762.2 also provides the polysaccharide such as a kind of chitosan., in these patents, the involved cross-linking agent used itself has toxicity.In addition, Chinese patent application 201110382475.8,201210033793.8 discloses bioactie agent, antibacterial, plasticizer and the foaming agent technologies of preparing in chitosan sthptic sponge such as adding thrombin.
In sum, from chitosan hemostatic material technology of preparing disclosed at present, also clinical demand cannot be met completely for various reasons.
Summary of the invention
Chitosan hemostatic material that the object of the present invention is to provide covalent cross-linking to be formed and preparation method thereof.
The technical solution used in the present invention is:
The chitosan hemostatic material that covalent cross-linking is formed, it utilizes cross-linking agent to carry out chemical crosslinking to chitosan by covalent bond to obtain; Described cross-linking agent is polyethyleneglycol diglycidylether.
The preparation method of the chitosan hemostatic material that covalent cross-linking is formed, step is as follows:
1) chitosan is made aqueous solution;
2) cross-linking agent is added in chitosan aqueous solution, be fully uniformly mixed, then pour in mould, lyophilization;
Described cross-linking agent is polyethyleneglycol diglycidylether.
The chemical formula of described polyethyleneglycol diglycidylether is:
。
n=1-20。
In polyethyleneglycol diglycidylether and chitosan molecule, the molar ratio of monosaccharide units is 0.001:1 ~ 1:1.
Chitosan solution is that wherein, the acid of use is organic acid and mineral acid by aqueous solution, the chitosan aqueous solution that is mixed with containing aqueous solution or the aqueous acid of organic solvent.
Chitosan solution is made for being dissolved in aqueous acetic acid by chitosan.
In described chitosan solution, the concentration of chitosan is 1%-3%(w/v).
In described acetum, the concentration of acetic acid is 1%-3%(v/v).
The material of described mould is the aluminium sheet material of politef plated film.
The invention has the beneficial effects as follows:
The present invention adopts polyethyleneglycol diglycidylether, is cross-linked in acid condition to chitosan.Wherein, the ethylene oxide group in polyethyleneglycol diglycidylether in acid condition, with the hydroxyl generation ring-opening reaction on chitosan, forms crosslinked product by generating ehter bond.The cross-linking agent that the inventive method uses is comparatively safe, and preparation is simple, and production cost is lower.
Accompanying drawing explanation
Fig. 1 is for adding cross-linking agent GDGE(0.05eq) prepared by chitosan sponge, be immersed in 2% aqueous acetic acid the form after shaking 30min.
Fig. 2 is for adding cross-linking agent GDGE(0.05eq) (right side) and the chitosan sponge do not added prepared by cross-linking agent (left side), soak the form after leaving standstill 10min in aqueous.
Fig. 3 is the blood coagulation rate (process 1min) of different cross-linking agent 2% chitosan sponge of covalent cross-linking under different mol ratio example and the comparison diagram of existing hemostasia products blood coagulation rate on market.
Fig. 4 is the blood coagulation rate (process 3min) of different cross-linking agent 2% chitosan sponge of covalent cross-linking under different mol ratio example and the comparison diagram of existing hemostasia products blood coagulation rate on market.
Fig. 5 is the blood coagulation rate (process 1min) of different cross-linking agent 3% chitosan sponge of covalent cross-linking under different mol ratio example and the comparison diagram of existing hemostasia products blood coagulation rate on market.
Fig. 6 is the blood coagulation rate (process 3min) of different cross-linking agent 3% chitosan sponge of covalent cross-linking under different mol ratio example and the comparison diagram of existing hemostasia products blood coagulation rate on market.
Detailed description of the invention
The chitosan hemostatic material that covalent cross-linking is formed, it utilizes cross-linking agent to carry out chemical crosslinking to chitosan by covalent bond to obtain; Described cross-linking agent is polyethyleneglycol diglycidylether.
The preparation method of the chitosan hemostatic material that covalent cross-linking is formed, step is as follows:
1) chitosan is made aqueous solution;
2) cross-linking agent is added in chitosan aqueous solution, be fully uniformly mixed, then pour in mould, lyophilization;
Described cross-linking agent is polyethyleneglycol diglycidylether.
The chemical formula of described polyethyleneglycol diglycidylether is:
。
Preferably, n=1-20 further preferably, is n=1 or 10 or 20.
In polyethyleneglycol diglycidylether and chitosan molecule, the molar ratio of monosaccharide units is 0.001:1 ~ 1:1; Preferably, be 0.05:1 or 0.10:1 or 0.20:1.In chitosan molecule monosaccharide units mole be determined as common practise.
Chitosan solution is that wherein, the acid of use is organic acid and mineral acid by aqueous solution, the chitosan aqueous solution that is mixed with containing aqueous solution or the aqueous acid of organic solvent; Preferably, be aqueous acid; Further preferred, be aqueous acetic acid.
Chitosan solution is made for being dissolved in aqueous acetic acid by chitosan.
In described chitosan solution, the concentration of chitosan is 1%-3%(w/v); Preferably, be 2% or 3%.
In described acetum, the concentration of acetic acid is 1%-3%(v/v); Preferably, be 2%.
The material of described mould is the aluminium sheet material of politef plated film.
Below in conjunction with specific embodiment, the present invention is described further:
embodiment 1:
Take chitosan (viscosity 100mPas, deacetylation 90%) (0.34g, the mole of monosaccharide units is 21.2mmol) and be dissolved in 2% acetum (v/v, 17ml), obtain 2% chitosan solution (w/v), at 40 DEG C of shaking table vibration 24h, make it dissolve completely.Add polyethyleneglycol diglycidylether (n=1) (18.4mg, 0.05eq), pouring diameter after mechanical agitation mixing into is leave standstill 12h in the mould of 6cm, and lyophilization, obtains the spongy goods that thickness is 5mm.
embodiment 2:
Identical with embodiment 1 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=1) is 36.8mg(0.10eq).
embodiment 3:
Identical with embodiment 1 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=1) is 73.6mg(0.20eq).
embodiment 4:
Take chitosan (viscosity 100mPas, deacetylation 90%) (0.51g) and be dissolved in 2% acetum (v/v, 17ml), obtain 3% chitosan solution (w/v), at 40 DEG C of shaking table vibration 24h, make it dissolve completely.Add polyethyleneglycol diglycidylether (n=1) (27.6mg, 0.05eq), pouring diameter after mechanical agitation mixing into is leave standstill 12h in the mould of 6cm, and lyophilization, obtains the spongy goods that thickness is 5mm.
embodiment 5:
Identical with embodiment 4 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=1) is 55.1mg(0.10eq).
embodiment 6:
Identical with embodiment 4 step, the amount that its difference is to add polyethyleneglycol diglycidylether (n=1) is 110.2mg (0.20eq).
embodiment 7:
Take chitosan (viscosity 100mPas, deacetylation 90%) (0.34g) and be dissolved in 2% acetum (v/v, 17ml), obtain 2% chitosan solution (w/v), at 40 DEG C of shaking table vibration 24h, make it dissolve completely.Add polyethyleneglycol diglycidylether (n=10) (52.7mg, 0.05eq), pouring diameter after mechanical agitation mixing into is leave standstill 12h in the mould of 6cm, and lyophilization, obtains the spongy goods that thickness is 5mm.
embodiment 8:
Identical with embodiment 7 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=10) is 105.4mg(0.10eq).
embodiment 9:
Identical with embodiment 7 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=10) is 210.8mg(0.20eq).
embodiment 10:
Take chitosan (viscosity 100mPas, deacetylation 90%) (0.51g) and be dissolved in 2% acetum (v/v, 17ml), obtain 3% chitosan solution (w/v), at 40 DEG C of shaking table vibration 24h, make it dissolve completely.Add polyethyleneglycol diglycidylether (n=10) (79.1mg, 0.05eq), pouring diameter after mechanical agitation mixing into is leave standstill 12h in the mould of 6cm, and lyophilization, obtains the spongy goods that thickness is 5mm.
embodiment 11:
Identical with embodiment 10 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=10) is 158.2mg(0.10eq).
embodiment 12:
Identical with embodiment 10 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=10) is 316.4mg(0.20eq).
embodiment 13:
Take chitosan (viscosity 100mPas, deacetylation 90%) (0.34g) and be dissolved in 2% acetum (, v/v, 17ml), obtain 2% chitosan solution (w/v), at 40 DEG C of shaking tables vibration 24h, make it dissolve completely.Add polyethyleneglycol diglycidylether (n=20) (105.4mg, 0.05eq), pouring diameter after mechanical agitation mixing into is leave standstill 12h in the mould of 6cm, and lyophilization, obtains the spongy goods that thickness is 5mm.
embodiment 14:
Identical with embodiment 13 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=20) is 210.8mg(0.10eq).
embodiment 15:
Identical with embodiment 13 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=20) is 421.6mg(0.20eq).
embodiment 16:
Take chitosan (viscosity 100mPas, deacetylation 90%) (0.51g) and be dissolved in 2% acetum (v/v, 17ml), obtain 3% chitosan solution (w/v), at 40 DEG C of shaking table vibration 24h, make it dissolve completely.Add polyethyleneglycol diglycidylether (n=20) (158.2mg, 0.05eq), pouring diameter after mechanical agitation mixing into is leave standstill 12h in the mould of 6cm, and lyophilization, obtains the spongy goods that thickness is 5mm.
embodiment 17:
Identical with embodiment 16 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=20) is 316.4mg(0.10eq).
embodiment 18:
Identical with embodiment 16 step, its difference is that the amount adding polyethyleneglycol diglycidylether (n=20) is 632.8mg(0.20eq).
solubility experiment
In order to prove that the chitosan sponge prepared is by being cross-linked to form, carry out dissolubility test to not adding cross-linking agent and adding the chitosan sponge goods that cross-linking agent obtains.
1,2%(V/V) aqueous acetic acid
Choose the sponge product adding minimum cross-linking agent, namely embodiment 1 and do not add cross-linking agent formed each 15mg of sponge, be placed in 10ml centrifuge tube respectively, respectively add 2% aqueous acetic acid 5ml.Put into agitator (rotating speed is 200-300rpm) and shake 30min, result shows, and the sponge not adding cross-linking agent is dissolved completely in 2% aqueous acetic acid, and embodiment 1 is only swelling does not dissolve.Swelling situation as shown in Figure 1.
2, aqueous solution
Choose the sponge product adding minimum cross-linking agent, i.e. embodiment 1 and do not add each about 1 × 1cm of sponge that cross-linking agent formed, be placed in batch cultur ware, respectively add aqueous solution 5ml.Leave standstill 10min, result shows, and the sponge not adding cross-linking agent is gel, and embodiment 1 becomes swelling spongy.As shown in Figure 2.
absorbency is tested
Sthptic sponge goods in specific embodiments are carried out to the test of absorbency with reference to experimental technique in (paying dogface, Wu Zhigu, modern wound dressings theory and practice [M], Beijing: Chemical Industry Press, 2007:651).Because phosphoric acid buffer liquor ratio water is closer to human body fluid, change phosphate buffer pH 7.4 into reference to testing distilled water used in document in testing.
1, prepared in difference Example 1-18 sthptic sponge goods, ensure that goods weigh in the dry state, are designated as W
dry(g);
2, phosphate buffer pH 7.4, soaking at room temperature 2h will be added in goods;
3, after 2h, the phosphate buffer suction pipe be not absorbed by the sponge and filter paper are blotted, weigh and be designated as W
wet(g).
4, formula 1 is utilized to calculate the absorbency of each goods.
Absorbency=(Wwet-Wdry)/Wdry (formula 1)
the absorbency of the chitosan sponge of table 1. covalent cross-linking
+
+absorbency: the liquid quality (g) that every 1g chitosan sponge goods absorb
* 2%CS goods: 2% chitosan solution resulting product; GDGE: polyethyleneglycol diglycidylether (n=1); PEG500: polyethyleneglycol diglycidylether (n=10); PEG1000: polyethyleneglycol diglycidylether (n=20)
*bracket inner digital is the molar ratio of cross-linking agent and chitosan monosaccharide units.
As can be seen from Table 1, the imbibition quality of sthptic sponge goods of the present invention is 21 ~ 39 times of sponge itself.Variable concentrations goods slightly difference, 2% chitosan sponge goods are slightly high compared with 3% chitosan sponge goods.
clotting assay
With reference to (Pei-Leun Kang, Shwu Jen Chang, Ioannis Manousakas, Chen Wei Lee, Chun-Hsu Yao, Feng-Huei Lin, Shyh Ming Kuo Development and assessment of hemostasis chitosan dressings
carbohydrate Polymers [J]2011,85:565 – 570) in experimental technique clotting assay is carried out to the sthptic sponge goods in specific embodiments.
1, prepared in Example 1-18 sthptic sponge goods, are cut to 1cm × 1cm size respectively, are put into beaker;
2, slowly fresh for 0.25ml Sanguis Gallus domesticus is added (Sanguis Gallus domesticus: anticoagulant heparin agent=5:1) in sthptic sponge goods;
3, at room temperature after (25 DEG C) place the time (1min, 3min) preset, 20ml purified water is slowly poured in beaker along walls of beaker, try not to have influence on blood solidifying on sponge in toppling process;
4, place after ten minutes and can be dissolved in solution by the erythrocyte that sthptic sponge goods absorb, utilize ultraviolet spectrophotometer to detect absorption value at wavelength 540nm place, and be dissolved in 20ml purified water as negative control with 0.25ml Sanguis Gallus domesticus;
5, formula 2 is utilized to calculate the blood coagulation rate of sthptic sponge goods.
Blood coagulation rate=(1-goods absorbance/contrast absorbance) × 100% (formula 2)
the blood coagulation rate (process 1min) of 2% chitosan sponge of table 2. covalent cross-linking
* matched group is the existing absorbable gelatin sponge product in market.
* GDGE: polyethyleneglycol diglycidylether (n=1); PEG500: polyethyleneglycol diglycidylether (n=10); PEG1000: polyethyleneglycol diglycidylether (n=20)
* *cross-linking agent equivalent: the molar ratio of cross-linking agent and chitosan monosaccharide units
+blood coagulation rate is six meansigma methodss measured, and bracket inner digital is SD(and standard deviation)
the blood coagulation rate (process 3min) of 2% chitosan sponge of table 3. covalent cross-linking
* matched group is the existing absorbable gelatin sponge product in market.
* GDGE: polyethyleneglycol diglycidylether (n=1); PEG500: polyethyleneglycol diglycidylether (n=10); PEG1000: polyethyleneglycol diglycidylether (n=20)
* *cross-linking agent equivalent: the molar ratio of cross-linking agent and chitosan monosaccharide units
+blood coagulation rate is six meansigma methodss measured, and bracket inner digital is SD
the blood coagulation rate (process 1min) of 3% chitosan sponge of table 4. covalent cross-linking
* matched group is the existing absorbable gelatin sponge product in market.
* GDGE: polyethyleneglycol diglycidylether (n=1); PEG500: polyethyleneglycol diglycidylether (n=10); PEG1000: polyethyleneglycol diglycidylether (n=20)
* *cross-linking agent equivalent: the molar ratio of cross-linking agent and chitosan monosaccharide units
+blood coagulation rate is six meansigma methodss measured, and bracket inner digital is SD
the blood coagulation rate (process 3min) of 3% chitosan sponge of table 5. covalent cross-linking
* matched group is the existing absorbable gelatin sponge product in market.
* GDGE: polyethyleneglycol diglycidylether (n=1); PEG500: polyethyleneglycol diglycidylether (n=10); PEG1000: polyethyleneglycol diglycidylether (n=20)
* *cross-linking agent equivalent: the molar ratio of cross-linking agent and chitosan monosaccharide units
+blood coagulation rate is six meansigma methodss measured, and bracket inner digital is SD
As can be seen from table 2-5 and Fig. 3, Fig. 4, Fig. 5, Fig. 6, chitosan sthptic sponge goods blood coagulation rate of the present invention is between 93%-99%, and have good coagulant property, blood coagulation rate also has obvious advantage compared with the hemostasia products on market.During 1min and 3min, blood coagulation rate is without significant difference, illustrates that goods of the present invention have coagulating effectiveness fast.
Above experimental result shows, sthptic sponge goods anthemorrhagic performance of the present invention is excellent.The hemostatic mechanism of people mainly forms clot by activating thrombin after platelet aggregation.The blood coagulation of current known clotting mechanism at least need 90s just start (Luo Xiaoxun. chitose haemostatic [P] Chinese invention patent application, 200710028001.7,2007-5-14).The anastalsis of chitosan sponge it is believed that and absorbs serum fast by the capillarity of sponge, increases the erythrocyte on its surface and hematoblastic concentration, makes it be gathered in sponge surface and wound closure, is stopped by blood, reduce the loss of blood before blood clot is formed.Meanwhile, the positive charge on chitosan sponge surface can activate the clotting mechanism of erythrocyte participation, thus accelerates the blood coagulation containing anticoagulant such as heparinized blood.
Claims (10)
1. the chitosan hemostatic material of covalent cross-linking formation, is characterized in that: it utilizes cross-linking agent to carry out chemical crosslinking to chitosan by covalent bond to obtain; Described cross-linking agent is polyethyleneglycol diglycidylether.
2. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 1, is characterized in that: step is as follows:
1) chitosan is made aqueous solution;
2) cross-linking agent is added in chitosan aqueous solution, be fully uniformly mixed, then pour in mould, lyophilization;
Described cross-linking agent is polyethyleneglycol diglycidylether.
3. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 1, is characterized in that: the chemical formula of described polyethyleneglycol diglycidylether is:
。
4. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 1, is characterized in that: n=1-20.
5. the preparation method of chitosan hemostatic material that formed of covalent cross-linking according to claim 1, is characterized in that: in polyethyleneglycol diglycidylether and chitosan molecule, the molar ratio of monosaccharide units is 0.001:1 ~ 1:1.
6. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 1, it is characterized in that: chitosan solution is by aqueous solution, the chitosan aqueous solution that is mixed with containing aqueous solution or the aqueous acid of organic solvent, wherein, the acid of use is organic acid and mineral acid.
7. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 6, is characterized in that: chitosan solution is made for being dissolved in aqueous acetic acid by chitosan.
8. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 7, it is characterized in that: in described chitosan solution, the concentration of chitosan is 1%-3%(w/v).
9. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 7, it is characterized in that: in described acetum, the concentration of acetic acid is 1%-3%(v/v).
10. the preparation method of the chitosan hemostatic material of covalent cross-linking formation according to claim 1, is characterized in that: the material of described mould is the aluminium sheet material of politef plated film.
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| CN111214695A (en) * | 2020-01-10 | 2020-06-02 | 中美医药科技河北有限公司 | Novel 3D structure biological high molecular material prepared by covalent reaction and synthetic method thereof |
| CN111205485A (en) * | 2020-03-11 | 2020-05-29 | 江南大学 | Preparation method of reinforced modified carboxymethyl chitosan hydrogel |
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| CN112972777A (en) * | 2021-02-23 | 2021-06-18 | 南京医科大学附属口腔医院 | Electro-spinning PLGA/PCL fibrous membrane composite chitosan sponge scaffold for oral alveolar bone regeneration and preparation method thereof |
| CN114588309A (en) * | 2022-03-09 | 2022-06-07 | 湖南玉津医疗科技有限公司 | Preparation method of double-crosslinked multi-microporous hemostatic sponge |
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