CN105920658B - Porous hemostatic powder and preparation method thereof - Google Patents
Porous hemostatic powder and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0038—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0023—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/0085—Porous materials, e.g. foams or sponges
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
- C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
- C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses porous hemostatic powder and a preparation method thereof. The method obtains superfine ice crystals by quick cooling, ensures low temperature during irradiation so that the ice crystals are not melted, and can be shaped after irradiation. The method can prepare the porous cross-linked material with small aperture, large porosity and large specific surface area. Because the radiation crosslinking is adopted, no crosslinking agent is introduced in the preparation process, and the prepared material has no biotoxicity caused by the crosslinking agent, thereby being a safe and nontoxic environment-friendly production flow. The prepared material has good prospect in the fields of hemostatic materials, drug carriers and the like.
Description
Technical Field
The invention discloses a preparation method of porous hemostatic powder, in particular to a preparation method of porous cross-linking hemostatic powder without introducing a cross-linking agent in the preparation process.
Background
The porous cross-linked material has wide application and requirements in the fields of tissue engineering, hemostatic materials, medicines and molecular carriers, biocatalysis, inert fillers and the like due to high porosity, low density and easy functional modification and loading. However, because the material is required to be shaped after pore forming, the traditional method adopting the cross-linking agent is difficult to cross-link the shaped solid material, and only pore forming is carried out by a freeze-drying method, and the obtained material has large pore diameter and small specific surface area, and cannot meet the requirements of high adsorption and drug loading. In addition, other methods for obtaining porous cross-linked materials at present need to introduce organic or irritant chemical reagents, and do not meet the requirements of low toxicity of materials in the fields of tissue engineering, hemostatic materials, drugs and molecular carriers, biocatalysis, inert fillers and the like.
Chinese patent CN103265720A discloses a new method for preparing porous cross-linked chitosan microspheres, and particularly relates to a method for preparing cross-linked chitosan microspheres by using 1, 2-cyclohexanediol diglycidyl ether as a cross-linking agent. The porous cross-linked chitosan microsphere is prepared by taking chitosan, 1, 2-cyclohexanediol diglycidyl ether and chlorinated paraffin as raw materials and performing dissolution, dispersion and balling, pore making, cross-linking and drying. However, two reagents of 1, 2-cyclohexanediol diglycidyl ether and chlorinated paraffin, which increase the toxicity of the material, are introduced in the preparation process.
Chinese patent CN104861102A discloses a preparation method of porous crosslinked polystyrene microspheres, which comprises the steps of pore-forming, swelling, stabilizing and extracting to obtain microspheres with micropores on the surface and macropores inside. But also introduces organic reagents with toxicity, such as benzoyl peroxide as an initiator, divinyl benzene as a cross-linking agent, acetone as an extracting agent and the like in the preparation process, thereby increasing the toxicity of the material.
Chinese patent CN101574539B discloses a gelatin sponge and a preparation method thereof, and the gelatin sponge is obtained by performing radiation crosslinking on a gelatin aqueous solution to form hydrogel, and then performing swelling and freeze drying. However, the porous cross-linked gelatin sponge obtained in the patent has large pore diameter, mainly focuses on 20 to 70 microns, and results in lower specific surface area, thereby limiting the application development of the porous cross-linked gelatin sponge as a high-adsorption material.
Disclosure of Invention
Aiming at the problems, the patent provides a simple and easy process method, which can realize that the porous cross-linked material is obtained by a green and environment-friendly preparation method without adding a cross-linking agent.
In order to achieve the purpose, the patent is realized by the following technical means:
the porous hemostatic powder is obtained by quickly cooling a solution containing a material to be crosslinked, further performing low-temperature radiation crosslinking on the solution by using rays under the condition of being lower than zero degrees centigrade, and then performing freeze drying.
The solvent of the solution may be any liquid that crystallizes at low temperature and sublimes when raised to ambient temperature with low pressure, preferably water.
The solute of the solution, i.e. the material to be cross-linked, can be one or more of sodium carboxymethylcellulose, aloe polysaccharide, fibrin glue, oxidized cellulose and oxidized regenerated cellulose, alpha-cyanoacrylate tissue glue, chitosan and derivatives thereof, starch, agarose, carrageenan, gum arabic, dextran, alginic acid, alginates and derivatives thereof, collagen, gelatin, albumin and fibrin.
The material to be crosslinked may be dissolved in water, a solution of a small molecule compound, a solution of a growth factor, a drug solution, a polypeptide solution, a solution of a protein or a nucleic acid.
The mass percentage of the solution is 1% -30%.
The solution is rapidly cooled by placing the solution in a flowing state in an environment with the temperature ranging from-196 ℃ to-10 ℃.
The temperature range for the low-temperature ray irradiation is-196 ℃ to 0 ℃.
The irradiation crosslinking rays adopt cobalt-60 gamma rays, cesium-137 gamma rays or electron beams for irradiation crosslinking, and the irradiation dose is 1-100 kGy.
The crosslinking degree of the hemostatic powder subjected to low-temperature ray irradiation crosslinking is in the range of 5-90%.
The material is crosslinked by radiation, and compared with an uncrosslinked material, the material has the advantages of improved water absorption rate and strength and slow degradation, so that the material is suitable for an absorbable hemostatic material.
The invention can realize cross-linking and simultaneously carry out grafting, polymerization or sterilization when the material is irradiated by low-temperature rays.
The porous hemostatic powder obtained by the invention can be subsequently loaded with growth factors, medicaments, polypeptides and proteins.
Compared with the porous hemostatic powder prepared under the normal-temperature radiation crosslinking, the porous hemostatic powder obtained by the low-temperature radiation crosslinking under the condition of lower than zero degree centigrade has the advantages of small pore diameter, large specific surface area and strong adsorbability, and compared with a method for crosslinking by using a crosslinking agent, no toxic substance is introduced.
Description of the drawings:
FIGS. 1 and 2 are SEM photographs of example 3 and example 5, respectively.
Detailed Description
The following examples, in which example 5 is a control, are intended to illustrate the invention, but not to limit the scope thereof.
Example 1
15 g of gelatin is dissolved in 85 g of water and stirred uniformly to obtain a 15% gelatin solution. Pouring the gelatin solution into a mold, rapidly placing into a refrigerator preset at-20 deg.C for quenching, rapidly cooling from room temperature to-20 deg.C, storing for 24 hr, rapidly transferring into a portable refrigerator (containing ice-water mixture) with a measurement temperature of 0 deg.C, and irradiating with cobalt-60 gamma ray at a dose of 30kGy to obtain hydrogel. Transferring the hydrogel to a freeze dryer for pre-freezing at-80 ℃, drying to obtain a porous material, crushing the obtained porous material, sieving with a 100-mesh sieve to obtain a porous cross-linked powder with a cross-linking degree of 48.7 +/-2.1%, and testing with an ASAP 2010BET specific surface area tester (Micromeritics, USA) with a BET specific surface area of 103.71m2The water absorption rate of the water-absorbing agent per gram for 24 hours is 2216.0 +/-7.5 percent.
Example 2
1 g of collagen is dissolved in 99 g of water and stirred uniformly to obtain a 1% collagen solution. Pouring the collagen solution into a mould, quickly putting the mould into an ultralow-temperature refrigerator set to be-70 ℃ for quenching, quickly cooling the temperature from room temperature to-70 ℃, then storing the solution for 24 hours, quickly transferring the solution into a portable refrigerator with the temperature of-10 ℃, and irradiating 1kGy by using electron beam rays to obtain the collagen hydrogel. And transferring to a freeze dryer for pre-freezing at the temperature of-20 ℃, and freeze-drying to obtain the porous collagen cross-linked sponge with the water absorption of 1634.0 +/-279.0% after 24 hours.
Example 3
15 g of carboxymethyl chitosan is dissolved in 85 g of water and stirred uniformly to obtain a 15 percent carboxymethyl chitosan solution. Pouring the solution into a mold, quickly putting the mold into liquid nitrogen with the temperature of-196 ℃ for quenching, and quickly reducing the temperature of the mold from room temperature to-196 ℃. Then storing for 24 hours, quickly transferring into a portable refrigerator with preset temperature of-20 ℃, irradiating by cobalt-60 gamma rays with the dose of 30kGy, transferring into a freeze dryer for pre-freezing at the pre-freezing temperature of-70 ℃, and then drying to obtain the productThe porous material was pulverized, sieved with a 100-mesh sieve, and tested with an ASAP 2010BET specific surface tester (Micromeritics, USA) to obtain a BET specific surface area of 52.17m2The cross-linking degree is 24.6 +/-3.3 percent, and the water absorption rate after 24 hours is 1800.7 +/-10.6 percent.
Fig. 1 shows the microstructure of the porous powder prepared according to the method of example 3, observed using a scanning electron microscope.
Example 4
15 g of carboxymethyl chitosan is dissolved in 85 g of water and stirred uniformly to obtain a 15 percent carboxymethyl chitosan solution. Pouring the solution into a mold, quickly putting the mold into an ultralow temperature refrigerator with the temperature of minus 80 ℃ for quenching, and quickly cooling the mold from room temperature to minus 80 ℃. And then storing for 24 hours, quickly transferring to a portable refrigerator with the preset temperature of-20 ℃, and irradiating by using cobalt-60 gamma rays with the dose of 30kGy to obtain the hydrogel. Transferring to a freeze drier for pre-freezing at-70 deg.C, drying, pulverizing the obtained porous material, sieving with 100 mesh sieve, and testing with ASAP 2010BET specific surface tester (Micromeritics, USA) to obtain BET specific surface area of 27.05m2The cross-linking degree is 29.1 +/-5.5 percent, and the water absorption rate after 24 hours is 1739.3 +/-13.0 percent.
Example 5
15 g of carboxymethyl chitosan is dissolved in 85 g of water and stirred uniformly to obtain a 15 percent carboxymethyl chitosan solution. Pouring the solution into a mould, and irradiating by using cobalt-60 gamma rays at normal temperature with the dose of 30kGy to obtain the hydrogel. Transferring to a freeze drier for pre-freezing at-70 deg.C, drying, pulverizing the obtained porous material, sieving with 100 mesh sieve, and testing with ASAP 2010BET specific surface tester (Micromeritics, USA) to obtain BET specific surface area of 2.06m2The cross-linking degree is 34.0 +/-3.1 percent, and the water absorption rate after 24 hours is 1703.3 +/-38.6 percent.
Fig. 2 shows the microstructure of the porous powder prepared according to the method of example 5, observed using a scanning electron microscope.
Example 6
10 g of sodium carboxymethylcellulose is dissolved in 90 g of water and stirred uniformly to obtain a 10% sodium carboxymethylcellulose solution. Pouring the solution into a moldRapidly cooling in a refrigerator preset at-196 deg.C to rapidly cool the temperature from room temperature to-196 deg.C, storing for 24 hr, rapidly transferring into a portable refrigerator with a measuring temperature of-10 deg.C, directly irradiating with cobalt-60 gamma ray with dosage of 35kGy, transferring the obtained hydrogel into a freeze drier for pre-freezing at-30 deg.C, drying, pulverizing the obtained porous material, sieving with 100 mesh sieve to obtain porous cross-linked powder with BET specific surface area of 81.58m2The cross-linking degree is 9.7 +/-0.6 percent, and the water absorption rate in 24 hours is 912.4 +/-126.9 percent.
Fig. 1 and 2 schematically show the microstructures of the porous powders prepared according to the methods of example 3 and example 5 observed by a scanning electron microscope. In addition to the difference of BET specific surface area data, it can be further seen from the scanning electron microscope photograph that the specific surface area of the porous crosslinked hemostatic powder prepared by crosslinking under the condition of less than zero degrees centigrade by low-temperature radiation irradiation (example 3) is larger than that of the porous crosslinked material prepared by normal-temperature irradiation (example 5) and then freeze-drying, and the pore diameter of the porous crosslinked hemostatic powder prepared by crosslinking under the condition of less than zero degrees centigrade by low-temperature radiation irradiation (example 3) is smaller than that of the porous crosslinked material prepared by normal-temperature irradiation (example 5) and then freeze-drying.
It should be noted that the above embodiments are only preferred within the scope of the claims, and the range of the solution concentration, the temperature range of the rapid cooling, the temperature range of the low-temperature ray irradiation, the pre-freezing temperature range and the irradiation dose are subject to the protection scope claimed by the claims. Modifications to the above parameters will be readily apparent to those skilled in the art without departing from the scope of the claims.
Under the same other conditions, the specific surface area of the porous cross-linked hemostatic powder prepared by the invention is larger than that of a porous cross-linked material obtained by normal-temperature irradiation and then freeze-drying, the pore diameter of the porous cross-linked material is smaller than that of the porous cross-linked material obtained by normal-temperature irradiation and then freeze-drying, and the blood coagulation and hemostasis effects of the porous cross-linked material are also better than those of the porous cross-linked material obtained by normal-temperature irradiation and then freeze-drying.
The porous cross-linked material prepared by the invention does not introduce a cross-linking agent or an emulsifying agent, so that the cytotoxicity is lower than that of the porous cross-linked material prepared by using the cross-linking agent or the emulsifying agent.
Claims (9)
1. A process for preparing porous styptic powder includes such steps as quick cooling the fluid solution containing the material to be cross-linked in-196-10 deg.C environment, low-temp cross-linking by radiation at zero deg.C or lower, and freeze drying.
2. The method of claim 1, wherein the concentration of the crosslinking material solution is in the range of 1% to 30%.
3. The method according to claim 1, wherein the rapid cooling is carried out at a temperature ranging from-196 ℃ to-20 ℃.
4. The production method according to claim 1, wherein the low-temperature ray irradiation is performed at a temperature ranging from-196 ℃ to 0 ℃.
5. The production method according to claim 1, wherein the radiation subjected to the low-temperature radiation irradiation is cobalt-60 γ -ray, cesium-137 γ -ray or electron beam radiation.
6. The production method according to claim 1, characterized in that the low-temperature ray irradiation is performed in a dose range of 1 to 100 kGy.
7. The method according to claim 1, wherein the solute of the solution, i.e. the cross-linking material, is one or more of sodium carboxymethylcellulose, aloe polysaccharides, fibrin glue, oxidized cellulose and oxidized regenerated cellulose, alpha-cyanoacrylate tissue glue, chitosan and its derivatives, starch, agarose, carrageenan, gum arabic, dextran, alginic acid, alginates and their derivatives, collagen, gelatin, albumin, fibrin.
8. The method according to claim 1, wherein the freeze-drying is carried out at a freezing temperature in the range of-196 ℃ to-10 ℃.
9. The porous hemostatic powder prepared by the method according to any one of claims 1 to 8, wherein the specific surface area of the porous hemostatic powder prepared by low-temperature radiation crosslinking under conditions of less than zero degrees centigrade is 5m2/g-150m2The specific surface area of the porous hemostatic powder is larger than that of the porous hemostatic powder prepared by ray irradiation crosslinking under the normal temperature condition.
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| WO2022141884A1 (en) * | 2020-12-31 | 2022-07-07 | 广州迈普再生医学科技股份有限公司 | Absorbable hemostatic powder, preparation method therefor and application thereof |
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| CN109646710B (en) * | 2019-02-14 | 2019-08-30 | 重庆医药高等专科学校 | A kind of hemostatic material and preparation method thereof of clinical department of internal medicine hemostasis |
| CN113134113B (en) * | 2021-04-07 | 2022-07-01 | 赛克赛斯生物科技股份有限公司 | Preparation method of absorbable hemostatic fluid gelatin and absorbable hemostatic fluid gelatin |
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