CN107596431B - Natural polysaccharide-based multifunctional microspheres and preparation method and application thereof - Google Patents
Natural polysaccharide-based multifunctional microspheres and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a natural polysaccharide-based multifunctional microsphere, a preparation method and application thereof, wherein the preparation method comprises the following steps: preparing natural polysaccharide into water dispersion, adding carboxymethyl saccharide, and stirring to obtain water phase; dissolving emulsifier in fat-soluble solvent to obtain oil phase, dripping water phase into oil phase, and stirring; dripping a cross-linking agent and stirring; standing, cleaning with a first polar solvent, removing oil phase, cleaning water layer with a second polar solvent, precipitating to obtain microspheres, extracting water layer, and drying to obtain the final product. The product can effectively block bleeding sites and promote hemostasis, does not contain any chemical cross-linking agent or other auxiliary agent, has high biological safety, does not cause hemolysis, and can be degraded and absorbed in a short period.
Description
Technical Field
The invention belongs to the technical field of hemostatic materials, relates to the fields of biomedical polymer materials and compatibility modification, and particularly relates to degradable and absorbable natural polysaccharide-based multifunctional microspheres and a preparation method and application thereof.
Background
Uncontrolled bleeding is a significant cause of war, traffic accidents, and other accidental injuries, as well as a problem often faced in first aid trauma and surgical procedures. How to effectively finish wound hemostasis is of great importance to saving the life of a patient, so that the development of a rapid and effective hemostatic material becomes a research hotspot in the world.
The powdery hemostatic material is widely applied to the field of surgical operation hemostasis due to simple and convenient operation and good wound surface attaching effect. At present, the powder hemostatic materials are mainly classified into aluminosilicates, chitosan and biological products, such as Quickclot, Celox, HemCon, tachcocomb H, etc. However, the aluminosilicate hemostatic products have good hemostatic performance and are non-biodegradable products, but later application finds that the aluminosilicate hemostatic products are easy to generate a large amount of heat, so that tissues are burnt, and secondary damage is brought to patients. The polysaccharide product has the greatest advantages that the product has good biocompatibility and degradability, Arista microspheres produced by Medador in America have a fissure structure on the surface, so that the adsorption capacity of the product on water is enhanced, and a chemical crosslinking agent epichlorohydrin and sodium tripolyphosphate are used in the preparation process, so that a certain toxicity is generated due to the residue of the crosslinking agent in the degradation process, and the application of the product is limited. After the hemostasis function is completed, the microspheres have strong hydrophilicity, so that bacterial breeding and infection of wound surfaces are easily caused, and the healing of wounds is further delayed. Some products achieve the aim of antibiosis by adding bacteriostatic components such as silver ions, antibiotics, quaternary ammonium salt, chitosan and other antibacterial agents. However, silver ions have strong cytotoxicity, and abuse of antibiotic drugs can also cause poor antibacterial effect, and cationic antibacterial agents such as quaternary ammonium salt and chitosan have certain antibacterial activity but do not have broad-spectrum antibacterial function. Dopamine, catechol and tannic acid are all from natural extraction products, have strong antibacterial performance and can be used as a hemostatic, and at present, no report for preparing natural polysaccharide-based multifunctional microspheres by using the natural extraction substances as cross-linking agents exists.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a natural polysaccharide-based multifunctional microsphere which has good hemostatic performance, does not contain any chemical cross-linking agent or other auxiliary agent, has high biological safety, does not cause hemolysis, can be degraded and absorbed in a short time, can promote wound healing and prevent wound surface bacterial infection.
The second purpose of the invention is to provide a preparation method of the natural polysaccharide-based multifunctional microspheres.
The third purpose of the invention is to provide the application of the natural polysaccharide-based multifunctional microspheres.
The technical scheme of the invention is summarized as follows:
a preparation method of natural polysaccharide-based multifunctional microspheres comprises the following steps: dispersing natural polysaccharide in ultrapure water at 70-90 ℃ to prepare dispersion liquid with the mass fraction of 5% -30%, then adding carboxymethyl saccharides which are 1% -6% of the mass of the natural polysaccharide, adding materials which are 0% -2% of the mass of the natural polysaccharide and have the effect of promoting wound healing, and uniformly stirring to obtain a water phase; dissolving an emulsifier in a fat-soluble solvent at the temperature of 45-75 ℃ to prepare a solution with the mass fraction of 0.03-1% as an oil phase, dripping the water phase into the oil phase according to the volume ratio of 1:15-3 under the conditions of 30-40 ℃ and 500-1000rpm, and continuously stirring for 30-120 min after dripping; reducing the stirring speed to 400-600rpm, dropwise adding a cross-linking agent which is 5-30% of the mass of the natural polysaccharide, and after the dropwise adding is finished, adjusting the stirring speed to 500-1000rpm and continuing stirring for 2-5 h; standing for 10-30min, washing with a first polar solvent for 3-5 times, removing oil phase, washing water layer with a second polar solvent for 3-5 times, precipitating to obtain microsphere, extracting water layer, and drying to obtain a natural polysaccharide-based multifunctional microsphere.
Preferably, the natural polysaccharide is at least one of hydroxyethyl cellulose, chitosan, starch, sodium alginate and hyaluronic acid;
preferably, the starch is corn starch, potato starch, tapioca starch or sweet potato starch; the viscosity of the chitosan is 200-400mPa.s, and the deacetylation degree is 50-80%; the viscosity of the sodium alginate is 200 +/-20 mPa.s; the viscosity of the hydroxyethyl cellulose is 1000-5000 mPa.s; the molecular weight of the hyaluronic acid is 4 x 105-2.2×106And D, dalton.
Preferably, the carboxymethyl saccharide is at least one of carboxymethyl chitosan with the viscosity of 200-6000mPa.s and the substitution degree of 80-95% and carboxymethyl cellulose with the viscosity of 600-4500mPa.s and the substitution degree of 60-95%.
Preferably, the material with the effect of promoting wound healing has a molecular weight of 1 × 105-3×105Hyaluronic acid of Dalton and molecular weight of 6X 103At least one epidermal growth factor.
Preferably, the emulsifier is at least one of Tween-60, Tween-80, Span-60, Span-80, Span-85 and Triton X-100; the fat-soluble solvent is at least one of liquid paraffin, vegetable oil, cyclohexane and n-hexane.
Preferably, the crosslinking agent is at least one of catechol, tannic acid, and dopamine.
Preferably, the first polar solvent is cyclohexane, n-hexane or petroleum ether. The second polar solvent is at least one of water, methanol and ethanol; the drying condition is vacuum drying or freeze drying at 30-60 deg.C.
The natural polysaccharide-based multifunctional microsphere prepared by the method.
The application of the natural polysaccharide multifunctional microspheres in preparing the styptic powder.
The invention has the advantages that:
the natural polysaccharide-based multifunctional microspheres prepared by the invention can effectively block bleeding sites, promote hemostasis, have good hemostasis performance, do not contain any chemical cross-linking agent or other auxiliary agent, have high biological safety, do not cause hemolysis, and can be degraded and absorbed in a short time. The product of the invention can stop bleeding of wound surface, and simultaneously has the effects of preventing bacterial breeding and promoting rapid healing of wound.
Drawings
FIG. 1 is a scanning electron microscope topography of a natural polysaccharide-based multifunctional microsphere.
FIG. 2 is a diagram of the hemostatic effect of natural polysaccharide-based multifunctional microspheres on SD rat liver injury bleeding.
FIG. 3 is a diagram of the effect of natural polysaccharide-based multifunctional microspheres on the wound healing experiment of SD rat skin.
FIG. 4 is a graph showing the effect of natural polysaccharide-based multifunctional microspheres on day 3 of wound healing of SD rat skin.
FIG. 5 is a diagram showing the results of wound healing experiments of the natural polysaccharide-based multifunctional microspheres applied to SD rat skin.
Detailed Description
The present invention is further illustrated by the following examples, which are provided to enable those skilled in the art to better understand the present invention and are not intended to limit the present invention in any way.
Example 1
A preparation method of natural polysaccharide-based multifunctional microspheres comprises the following steps: dispersing natural polysaccharide in ultrapure water at 70 ℃ to prepare dispersion liquid with the mass fraction of 5%, then adding carboxymethyl saccharides which are 1% of the mass of the natural polysaccharide, and uniformly stirring to obtain a water phase; dissolving an emulsifier in a fat-soluble solvent at 45 ℃ to prepare a solution with the mass fraction of 0.03% as an oil phase, dripping a water phase into the oil phase according to the volume ratio of 1:15 at 30 ℃ and 500rpm, and continuously stirring for 120min after dripping; reducing the stirring speed to 400rpm, dropwise adding a cross-linking agent which is 5% of the natural polysaccharide in mass, and after dropwise adding, adjusting the stirring speed to 500rpm and continuing stirring for 5 hours; standing for 30min, washing with first polar solvent for 5 times, removing oil phase, washing water layer with second polar solvent for 5 times, precipitating to obtain microsphere, extracting water layer, and vacuum drying at 30 deg.C to obtain a natural polysaccharide-based multifunctional microsphere (figure 1) with particle diameter of 15-50 μm.
The natural polysaccharide comprises hydroxyethyl cellulose, chitosan and corn starch in a mass ratio of 1:1: 1; the hydroxyethyl cellulose has a viscosity of 1000 mPa.s; the viscosity of the chitosan is 200mPa.s, and the deacetylation degree is 50%;
the carboxymethyl saccharide is carboxymethyl chitosan with viscosity of 200mPa.s and substitution degree of 80%.
The emulsifier is Tween-60, Tween-80 and Span-85 in a mass ratio of 1:1: 5;
the fat-soluble solvent is liquid paraffin.
The cross-linking agent is catechol and tannic acid with the mass ratio of 1: 2.
The first polar solvent is cyclohexane and n-hexane with the volume ratio of 1:2, and the second polar solvent is ethanol;
example 2
A preparation method of natural polysaccharide-based multifunctional microspheres comprises the following steps: dispersing natural polysaccharide in ultra-pure water at 90 ℃ to prepare a dispersion liquid with the mass fraction of 30%, then adding carboxymethyl saccharides which are 6% of the mass of the natural polysaccharide, adding materials which are 2% of the mass of the natural polysaccharide and have the effect of promoting wound healing, and uniformly stirring to obtain a water phase; dissolving an emulsifier in a fat-soluble solvent at 75 ℃ to prepare a solution with the mass fraction of 1% as an oil phase, dropwise adding a water phase into the oil phase according to the volume ratio of 1:3 at 40 ℃ and 1000rpm, and continuously stirring for 30min after dropwise adding; reducing the stirring speed to 600rpm, dropwise adding a cross-linking agent which is 30% of the natural polysaccharide in mass, and after dropwise adding, adjusting the stirring speed to 1000rpm and continuing stirring for 2 h; standing for 10min, washing with a first polar solvent for 3 times, removing oil phase, washing water layer with a second polar solvent for 3 times, precipitating to obtain microsphere, extracting water layer, and freeze drying to obtain the final product. The particle size is 20-60 um.
The natural polysaccharide comprises potato starch, sodium alginate and hyaluronic acid in a mass ratio of 1:1:1, wherein the viscosity of the sodium alginate is 200 +/-20 mPa.s; the molecular weight of hyaluronic acid is 4 × 105And D, dalton.
The carboxymethyl saccharide is carboxymethyl chitosan with viscosity of 6000mPa.s and substitution degree of 95% and carboxymethyl cellulose with viscosity of 600mPa.s and substitution degree of 60% in a mass ratio of 1: 1.
The material with the effect of promoting wound healing has a molecular weight of 1 × 105(ii) hyaluronic acid of dalton.
The emulsifier is Tween-80 and Span-60 in a mass ratio of 4: 1; the fat-soluble solvent is liquid soybean oil.
The cross-linking agent is tannic acid and dopamine with the mass ratio of 1: 1.
The first polar solvent is petroleum ether. The second polar solvent is methanol.
Example 3
A preparation method of natural polysaccharide-based multifunctional microspheres comprises the following steps: dispersing natural polysaccharide in ultrapure water at 80 ℃ to prepare dispersion liquid with the mass fraction of 15%, then adding carboxymethyl saccharides which are 3% of the mass of the natural polysaccharide, adding materials which are 1% of the mass of the natural polysaccharide and have the effect of promoting wound healing, and uniformly stirring to obtain a water phase; dissolving an emulsifier in a fat-soluble solvent at 60 ℃ to prepare a solution with the mass fraction of 0.5% as an oil phase, dripping the water phase into the oil phase according to the volume ratio of 1:5 at 35 ℃ and 800rpm, and continuously stirring for 60min after dripping; reducing the stirring speed to 500rpm, dropwise adding a cross-linking agent which is 12% of the natural polysaccharide in mass, and after the dropwise adding is finished, adjusting the stirring speed to 700rpm and continuously stirring for 3 hours; standing for 20min, washing with a first polar solvent for 4 times, removing oil phase, washing water layer with a second polar solvent for 4 times, precipitating to obtain microsphere, extracting water layer, and vacuum drying at 60 deg.C to obtain a natural polysaccharide-based multifunctional microsphere.
The natural polysaccharide comprises chitosan, tapioca starch (sweet potato starch can be used for replacing the tapioca starch) and hydroxyethyl cellulose in a mass ratio of 1:1: 5; the viscosity of the chitosan is 400mPa.s, and the deacetylation degree is 80%; the hydroxyethyl cellulose has a viscosity of 5000 mpa.s.
The carboxymethyl saccharide is carboxymethyl chitosan with viscosity of 5000mPa.s and substitution degree of 90% and carboxymethyl cellulose with viscosity of 4000mPa.s and substitution degree of 90% in a mass ratio of 2: 1.
The material with the effect of promoting wound healing is prepared from the following materials in a mass ratio of 5: 1 has a molecular weight of 3X 105Dalton hyaluronic acid and molecular weight of 6X 103Dalton epidermal growth factor.
The emulsifier is Span-80 and Triton X-100 in a mass ratio of 1: 1;
the fat-soluble solvent is cyclohexane and n-hexane with the volume ratio of 1: 2.
The cross-linking agent is dopamine.
The first polar solvent is petroleum ether. The second polar solvent is an ethanol solution with the mass fraction of 80%.
Example 4
A preparation method of natural polysaccharide-based multifunctional microspheres comprises the following steps: dispersing natural polysaccharide in ultrapure water at 78 ℃ to prepare dispersion liquid with the mass fraction of 10%, then adding carboxymethyl saccharides which are 4% of the mass of the natural polysaccharide, adding materials which are 0.5% of the mass of the natural polysaccharide and have the effect of promoting wound healing, and uniformly stirring to obtain a water phase; dissolving an emulsifier in a fat-soluble solvent at 60 ℃ to prepare a solution with the mass fraction of 0.6% as an oil phase, dripping the water phase into the oil phase according to the volume ratio of 1:10 at 40 ℃ and 800rpm, and continuously stirring for 50min after dripping; reducing the stirring speed to 600rpm, dropwise adding a cross-linking agent which is equivalent to 5% of the mass of the natural polysaccharide, and continuously stirring for 3 hours with the stirring speed of 600rpm after the dropwise adding is finished; standing for 20min, washing with a first polar solvent for 5 times, removing oil phase, washing water layer with a second polar solvent for 3 times, precipitating to obtain microsphere, extracting water layer, and vacuum drying at 50 deg.C to obtain a natural polysaccharide-based multifunctional microsphere. The grain diameter is 15-25 um.
The natural polysaccharide is sodium alginate and hyaluronic acid with the mass ratio of 3: 1;
the viscosity of the sodium alginate is 200 +/-20 mPa.s; the molecular weight of the hyaluronic acid is 2.2 x 106And D, dalton.
The carboxymethyl saccharide is 5000mPa.s with the viscosity of 2:1 and the substitution degree of 90 percent, and the carboxymethyl cellulose with the viscosity of 4500mPa.s and the substitution degree of 95 percent.
The material with wound healing promoting effect has a mass ratio of 4:1 and a molecular weight of 3 × 105Dalton hyaluronic acid and molecular weight 6X 103Dalton epidermal growth factor.
The emulsifier is Span-80;
the fat-soluble solvent is liquid paraffin.
The cross-linking agent is tannic acid.
The first polar solvent is cyclohexane. The second polar solvent is a 70% methanol solution.
Experimental example 1
The performance detection of the natural polysaccharide-based multifunctional microspheres obtained in the examples 1 to 4 is carried out by the following specific detection method:
the hemolysis rate: the assay was performed according to the method specified in GB/T16175-.
Through detection, the natural polysaccharide-based multifunctional microspheres have good biocompatibility, and the hemolysis rate of the natural polysaccharide-based multifunctional microspheres in each embodiment is less than 5% (table 1), so that the natural polysaccharide-based multifunctional microspheres meet the national standard.
Table 1 shows the statistical results of hemolysis rates of different materials:
| sample name | Mean value (X. + -. s) | Hemolysis ratio (%) |
| Positive control group | 0.642±0.0387 | 100 |
| Negative control group | 0.048±0.0008 | 1.03 |
| Example 1 | 0.048±0.0025 | 1.12 |
| Example 2 | 0.048±0.0032 | 1.25 |
| Example 3 | 0.048±0.0035 | 1.30 |
| Example 4 | 0.048±0.0005 | 1.20 |
Note: the positive control in table 1 was distilled water; the negative control group was normal saline; the experimental group is the normal saline leaching liquor of the natural polysaccharide-based multifunctional microspheres in each embodiment; x is the absorbance at 545 nm; and s is the absorbance measurement deviation.
Experimental example 2
The in vitro hemostasis function detection is carried out on the natural polysaccharide-based multifunctional microspheres in each embodiment, and the specific detection method comprises the following steps: SD rats were anesthetized, fixed, and a cut of about 0.5cm × 1.0cm was made in the left outer lobe of the liver using surgical scissors, and after bleeding, 0.01g of natural polysaccharide-based multifunctional microspheres (blank control without any treatment) were sprayed on the bleeding site.
The natural polysaccharide-based multifunctional microsphere hemostatic microspheres prepared in example 3 stop bleeding (see fig. 2) and promote wound healing (see fig. 3). And has certain adhesiveness, and can be attached to the wound to form the effect of a protective layer.
Through detection, the natural polysaccharide multifunctional microspheres can effectively stop bleeding within 36-76s (Table 2).
Table 2 shows the statistical results of the hemostatic time of the liver of SD rats using the natural polysaccharide-based multifunctional microspheres of examples 1-4.
| Sample numbering | Blank control | Example 1 | Example 2 | Example 3 | Example 4 |
| Hemostasis time(s) | 207±10 | 56±20 | 50±5 | 60±10 | 55±5 |
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
The novel natural polysaccharide-based multifunctional microsphere prepared by the technology has good comprehensive performance, is convenient to operate and store, has a simple preparation process, and is suitable for industrial production.
Experimental example 3
The multifunctional hemostatic microspheres provided in example 2 and example 4 were subjected to a skin wound healing promotion experiment, which specifically includes: SD rats were anesthetized, fixed, and then a skin wound of about 2mm in depth was made on their backs using a punch of 5mm in diameter (see the first column of FIG. 5), and then 0.02g of hemostatic microspheres were applied to the wound (see the second and third rows of the second column of FIG. 5), and the healing of the skin wound on the backs of the rats was observed on days 3, 7 and 14, respectively, without any treatment in the blank control group, indicating that: compared with a control group, the hemostatic microspheres provided by the invention can promote the wound healing speed of the skin to a certain extent, wherein the positions of the dashed boxes represent the situation after the hemostatic microspheres are added. The hemostatic microspheres provided by the invention not only have a good hemostatic effect, but also have a certain adhesion property, and can be attached to a wound to form a protective layer (fig. 4).
Claims (7)
1. A preparation method of natural polysaccharide-based multifunctional microspheres comprises the following steps:
dispersing natural polysaccharide in ultrapure water at 70-90 ℃ to prepare dispersion liquid with the mass fraction of 5% -30%, then adding carboxymethyl saccharides which are 1% -6% of the mass of the natural polysaccharide, adding materials which are 0% -2% of the mass of the natural polysaccharide and have the effect of promoting wound healing, and uniformly stirring to obtain a water phase;
dissolving an emulsifier in a fat-soluble solvent at the temperature of 45-75 ℃ to prepare a solution with the mass fraction of 0.03-1% as an oil phase, dripping the water phase into the oil phase according to the volume ratio of 1:15-3 under the conditions of 30-40 ℃ and 500-1000rpm, and continuously stirring for 30-120 min after dripping;
reducing the stirring speed to 400-600rpm, dropwise adding a cross-linking agent which is 5-30% of the mass of the natural polysaccharide, and after the dropwise adding is finished, adjusting the stirring speed to 500-1000rpm and continuing stirring for 2-5 h;
standing for 10-30min, washing with a first polar solvent for 3-5 times, removing oil phase, washing water layer with a second polar solvent for 3-5 times, precipitating to obtain microsphere, extracting water layer, and drying to obtain natural polysaccharide-based multifunctional microsphere;
wherein the cross-linking agent is at least one of catechol, tannic acid and dopamine;
the material with the effect of promoting wound healing has a molecular weight of 1 × 105-3×105Hyaluronic acid of Dalton and molecular weight of 6X 103At least one of dalton epidermal growth factor;
the natural polysaccharide is at least one of hydroxyethyl cellulose, chitosan, starch, sodium alginate and hyaluronic acid.
2. The method of claim 1, wherein the starch is corn starch, potato starch, tapioca starch, or sweet potato starch; the viscosity of the chitosan is 200-400mPa.s, and the deacetylation degree is 50-80%; the viscosity of the sodium alginate is 200 +/-20 mPa.s; the viscosity of the hydroxyethyl cellulose is 1000-5000 mPa.s; the molecular weight of the hyaluronic acid is 4 x 105-2.2×106Dale (Chinese character of 'Da')And (6) pausing.
3. The method as claimed in claim 1, wherein the carboxymethyl saccharide is at least one of carboxymethyl chitosan having a viscosity of 200-.
4. The method of claim 1, wherein the emulsifier is at least one of Tween-60, Tween-80, Span-60, Span-80, Span-85, and Triton X-100; the fat-soluble solvent is at least one of liquid paraffin, vegetable oil, cyclohexane and n-hexane.
5. The method of claim 1, wherein the first polar solvent is cyclohexane, n-hexane, or petroleum ether; the second polar solvent is at least one of water, methanol and ethanol; the drying condition is vacuum drying or freeze drying at 30-60 deg.C.
6. A natural polysaccharide-based multifunctional microsphere prepared by the method of any one of claims 1 to 5.
7. Use of a natural polysaccharide-based multifunctional microsphere of claim 6 in the preparation of a hemostatic powder.
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