WO2021027006A1 - 新型可降解的止血材料及其制备方法 - Google Patents
新型可降解的止血材料及其制备方法 Download PDFInfo
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- WO2021027006A1 WO2021027006A1 PCT/CN2019/106172 CN2019106172W WO2021027006A1 WO 2021027006 A1 WO2021027006 A1 WO 2021027006A1 CN 2019106172 W CN2019106172 W CN 2019106172W WO 2021027006 A1 WO2021027006 A1 WO 2021027006A1
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—Polysaccharides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
- C08B15/02—Oxycellulose; Hydrocellulose; Cellulosehydrate, e.g. microcrystalline cellulose
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
-
- 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
Definitions
- the invention belongs to the field of medical dressings, and specifically relates to a novel degradable hemostatic material and a preparation method thereof.
- Oxidized cellulose is a gauze-like or cloth-like fibrous material in which cellulose is oxidized to cellulose acid. It looks like cotton yarn, soft and thin, and has good biocompatibility, degradability and safety. .
- oxidized cellulose has been successfully used in neurosurgery, otolaryngology, hepatobiliary surgery and other operations to stop bleeding, and the intraoperative operation is simple and easy.
- Surgicel is widely used clinically, which is a kind of woven yarn block of oxidized regenerated fiber. It belongs to the carboxymethyl cellulose hemostatic material. It is a water-soluble, fully-absorbable neutral cellulose with very good properties. It is water-soluble and has a strong affinity for water and saline. When it is dissolved in water, it forms a hydrocolloid with a certain viscosity, which expands and fills the gaps in the wound or compresses blood vessels to achieve hemostasis.
- the hemostatic yarn cannot play a role in the parts where the gauze cannot be filled, which limits its use.
- research has been carried out on oxidized cellulose hemostatic powder, which broadens the scope of clinical application of oxidized cellulose hemostatic materials.
- the oxidized cellulose hemostatic materials prepared by the prior art all have the disadvantages of low oxidation degree, high cost, large particle size and unevenness, and they need to be improved urgently.
- the purpose of the present invention is to provide a novel degradable hemostatic material and a preparation method thereof.
- the concept of the present invention is as follows:
- the present invention improves the degree of oxidation of cellulose by performing pre-oxidation crushing treatment, pre-oxidation swelling treatment and oxidation process on cellulose, so that the carboxyl content of oxidized cellulose can reach more than 22% , In line with the carboxyl content requirements of oxidized cellulose hemostatic materials; the present invention selects NO 2 oxidation system, hypochlorite oxidation system, TEMPO oxidation system, HNO 3 /H 3 PO 4 ⁇ NaNO 2 oxidation system for C 6 selection of cellulose Oxidation improves the oxidation efficiency, has fewer side reactions, and can effectively control the degree of oxidation; the present invention effectively improves the coagulation effect of the hemostatic material by complexing coagulation factors, and significantly shortens the hemostasis time compared with the positive control; the present invention uses static electricity The method of spraying controls the particle size of the hemostatic material, so that the hemostatic material has a smaller and uniform particle size; through
- the cellulose includes natural fiber materials such as wood fiber, cotton fiber, bacterial cellulose, and regenerated cellulose.
- the present invention provides a new type of degradable hemostatic material (microspheres), the hemostatic material is oxidized cellulose loaded with clotting factors, wherein the carboxyl content of the oxidized cellulose 20-30% (mass percentage), degree of polymerization of 200-400, particle size of 50-150 ⁇ m (preferably 90-120 ⁇ m), said coagulation factor accounts for 0.01-2 of said oxidized cellulose mass percentage %.
- the coagulation factor is a soluble calcium salt, preferably calcium chloride.
- the present invention provides a method for preparing the hemostatic material, including the following steps:
- the pre-oxidation process the cellulose is crushed and swelled with sodium hydroxide solution in sequence;
- Oxidation process selectively oxidize the hydroxyl group at the C 6 position of the cellulose molecule, and introduce a carboxyl group at the C 6 position to obtain oxidized cellulose; and assist ultrasonic treatment in the oxidation process;
- Electrostatic spraying Dissolve the mixture obtained in step C in an alkali system, stir and filter, collect the filtrate, spray the filtrate into the coagulation liquid by means of electrostatic spray, collect the precipitate, and wash with water and/or ethanol until it is neutral;
- step D The product obtained in step D is mechanically crushed or ground, dried, sieved, and sterilized to obtain it.
- the coagulation liquid used in step D is ethanol, sulfuric acid solution or hydrochloric acid solution.
- step A includes: adding a certain amount of cellulose to a high-pressure homogenizer (or dynamic high-pressure homogenizer), refiner, decomposer, pulverizer (low temperature pulverizer) or ultrasonic machine (high-intensity ultrasonic In the machine), pulverize until the fiber length is less than 1mm; filter the slurry to obtain the precipitate. After washing with water (wash the precipitate with deionized water several times), place it in 1-20% sodium hydroxide solution to moisten The swelling treatment is 20-120min, and the swollen cellulose is washed with water and/or ethanol to neutrality.
- a high-pressure homogenizer or dynamic high-pressure homogenizer
- refiner refiner
- decomposer refiner
- pulverizer low temperature pulverizer
- ultrasonic machine high-intensity ultrasonic In the machine
- step B includes: adding cellulose to the oxidation system for oxidation reaction, the oxidation reaction and ultrasonic treatment are performed simultaneously; after the reaction, the precipitate is collected by filtration or centrifugation, and washed with water and/or ethanol to neutrality to obtain oxidation Cellulose.
- the oxidation system used in the present invention can be a NO 2 oxidation system, a hypochlorite oxidation system, a TEMPO oxidation system or a HNO 3 /H 3 PO 4 -NaNO 2 oxidation system.
- the NO 2 oxidation system uses CCl 4 as a solvent and a prepared NO 2 oxidation solution with a concentration of 10-30%.
- the hypochlorite oxidation system can be a 20-200% v/v NaClO solution.
- the TEMPO oxidation system may be a TEMPO-NaClO-NaBr oxidation system.
- the HNO 3 /H 3 PO 4 -NaNO 2 oxidation system may be a mixture of HNO 3 and H 3 PO 4 containing NaNO 2 .
- the step B includes: adding 1-20 g of cellulose to 100-200 mL of the NO 2 oxidation system, the reaction temperature is 5-30°C, and the reaction time It is 8-100h; the oxidation reaction and the ultrasonic treatment are carried out simultaneously; after the reaction, the precipitate is collected by filtration or centrifugation, and the precipitate is washed with CCl 4 and ethanol successively to obtain oxidized cellulose.
- the step B includes: suspending 5-20 g of cellulose in 100-200 mL of water, adjusting the pH of the suspension to 9-11, at 40-60°C Under the conditions, add 20 ⁇ 200mL of 20 ⁇ 100%v/v NaClO solution, and react for 2 ⁇ 10h; the oxidation reaction and ultrasonic treatment are carried out simultaneously; after the reaction, the precipitate is collected by filtration or centrifugation, and washed with water and/or ethanol to Neutral to obtain oxidized cellulose.
- the step B includes: suspending 10-100 g of cellulose in 100-1000 mL of Na 2 CO 3 /NaHCO 3 buffer with a pH of 9-11, and stirring for 2-10 minutes Then, add TEMPO to make the final concentration of TEMPO 0.1 ⁇ 1.0mg/mL, then add NaBr to make the final concentration of NaBr 1 ⁇ 10mg/mL; control the temperature of the reaction system to 20 ⁇ 30°C, wait until TEMPO and NaBr are completely dissolved Afterwards, adjust the pH of the reaction system to 9-11, and then add saturated NaClO solution step by step, adding once every 30-60 min.
- the volume of NaClO solution added is 20-100% of the total volume of the solution, and the reaction is 3-10h; oxidation reaction and The ultrasonic treatment is performed simultaneously; after the reaction, the precipitate is collected by filtration or centrifugation, and washed with water and/or ethanol to neutrality to obtain oxidized cellulose.
- the molar ratio of Na 2 CO 3 and NaHCO 3 in the Na 2 CO 3 /NaHCO 3 buffer is 1:3 to 3:1 (preferably 1:2).
- the step B includes: preparing HNO 3 and H 3 PO 4 analytical pure in a volume ratio of 0.5:1 to 3:1 To form a mixture, add cellulose to the above mixture to make the concentration 0.01 ⁇ 0.1g/mL, then add NaNO 2 powder to make the final concentration of NaNO 2 10 ⁇ 50mg/mL; at 20 ⁇ 50°C
- the lower reaction is 8 to 48 hours; the oxidation reaction and the ultrasonic treatment are carried out simultaneously; after the reaction, the precipitate is collected by filtration or centrifugation, and washed with water and/or ethanol to neutrality to obtain oxidized cellulose.
- the ultrasound can be a sink ultrasound or a probe ultrasound.
- the ultrasonic conditions in step B are: ultrasonic frequency 20-40kHz, power 100-1000W.
- step D the mixture obtained in step C is dissolved in an alkali system at -20 to -5°C.
- the alkaline system is a 5-20% sodium hydroxide solution, a 5-20% sodium hydroxide solution containing 5-30% urea, or a 5-20% lithium hydroxide solution containing 5-30% urea.
- the voltage of the electrostatic spray is 5-20 kV, and the feed rate is 20-400 ⁇ L/min.
- the drying method adopted in step E is spray drying, supercritical drying, vacuum drying, blast drying or freeze drying.
- the preparation method of the regenerated cellulose is as follows: natural fiber (such as wood fiber, cotton fiber, bacterial cellulose and other fibrous materials) is used as raw material, and the cellulose is made through alkalization, aging, sulfonation and other processes. .
- natural fiber such as wood fiber, cotton fiber, bacterial cellulose and other fibrous materials
- the present invention has at least the following advantages and beneficial effects:
- the invention provides a novel degradable hemostatic material and a preparation method thereof, which have the advantages of continuous process, high efficiency, low cost, etc., and prepare an oxidized cellulose hemostatic material with uniform and controllable microspheres, high oxidation degree and strong hemostatic ability.
- the new hemostatic material is suitable for hemorrhage, irregular parts and organ bleeding, and the material has good degradability and quick hemostasis.
- the present invention is specifically optimized for the existing oxidized cellulose hemostatic material preparation process as follows:
- the pre-oxidation process the fiber is crushed by a high-pressure homogenizer, refiner/decomposer, low-temperature pulverization, high-intensity ultrasound, and dynamic high-pressure homogenizer to activate cellulose, reduce crystallinity, and improve hydroxyl The degree is good for oxidation.
- Oxidation process selective oxidation of cellulose C 6 position.
- the oxidation system includes: NO 2 oxidation system, hypochlorite oxidation system, TEMPO oxidation system, HNO 3 /H 3 PO 4 ⁇ NaNO 2 oxidation system.
- the simultaneous ultrasonic treatment and oxidation process can effectively increase the carboxyl content in cellulose.
- Electrostatic spraying spraying the reaction liquid into the coagulation liquid by means of electrostatic spraying, so that the hemostatic material has a small and uniform particle size.
- the invention provides a hemostatic product meeting the clinical requirements of a degradable hemostatic material and a preparation method thereof.
- the specific plan is as follows:
- Pre-treatment Add a certain amount of cellulose to one of the high-pressure homogenizer, refiner/decomposer, low-temperature pulverizer, high-intensity ultrasonic machine, and dynamic high-pressure homogenizer, and perform repeated pulverization operations until The fiber length is significantly shortened.
- the slurry is filtered to obtain the precipitate. After washing the precipitate with deionized water for many times, it is swelled with a certain concentration of sodium hydroxide solution, and the swollen cellulose is filtered and washed with ethanol of different solubility to Standby after neutral.
- CCl 4 as the solvent to prepare NO 2 oxidation solution; add the prepared cellulose to the above oxidation solution, the reaction temperature is 5-30 °C, the reaction time is 8-100h, the oxidation process and the ultrasonic process are carried out simultaneously. Including one of sink type or probe type ultrasound. After the reaction, the oxide is washed with CCl 4 several times, and then the product is washed with a certain concentration of ethanol aqueous solution until the reagent residue meets the requirements, and the lower layer is separated for use. .
- the oxidation process is synchronized with the ultrasonic process. Including one of water tank type or probe type ultrasound. After the reaction, the product is repeatedly centrifuged and washed with deionized water or ethanol aqueous solution to separate the lower layer of precipitation for use.
- HNO 3 and H 3 PO 4 analytical grades Take HNO 3 and H 3 PO 4 analytical grades and configure them into a mixed solution in a volume ratio of 0.5:1 to 3:1.
- Electrostatic spray treatment dissolve the product obtained in step 3 at a low temperature in an alkali system, the low temperature is -20 ⁇ -5°C, the alkali system includes: sodium hydroxide system, sodium hydroxide/urea system, lithium hydroxide/urea system, hydrogen The solubility of sodium oxide or lithium hydroxide is 5-20% (m/v), and the concentration of urea is 5-30%. After stirring, it is filtered and the filtrate is sprayed into the coagulation liquid by electrostatic spraying.
- the voltage in the medium is 5-20kV
- the feed rate is 20-400 ⁇ L/min
- the coagulation liquid is one of sulfuric acid aqueous solution, hydrochloric acid aqueous solution, and ethanol solution, and then the collected microspheres are washed repeatedly with ethanol to neutrality. spare.
- Molding The product of the above process is crushed by one or more of ball mill, roller press, and hammer mill, and the processed product is dried.
- the drying methods include spray drying, supercritical drying, vacuum drying, One of blast drying and freeze drying, and then the dried powder is sieved and sterilized to obtain oxidized cellulose hemostatic powder.
- the mass percentage of ⁇ -cellulose accounts for more than 99% of the total fiber.
- CCl 4 as the solvent, prepare 1000ml of oxidizing solution containing 10% NO 2 ; add cellulose to the above oxidizing solution, the reaction temperature is 25°C, the reaction time is 20h, the oxidation process and the water tank ultrasonic process are performed simultaneously. Ultrasonic frequency 28kHz, power 500W, after the reaction, the reactant is filtered, the oxide is washed 3 times with 500ml CCl 4 , then the product is washed 4 times with 500ml of anhydrous ethanol aqueous solution, and the precipitate is filtered off with suction for use;
- step 4 Dissolve the product of step 3 in deionized water containing 10g of sodium hydroxide, 200g of urea and 2000ml at a temperature of -10°C. After the cellulose is fully dissolved, filter it, and spray the filtrate into the coagulation liquid by electrostatic spraying. , The voltage in the electrostatic spraying is 40kV, the feeding rate is 120 ⁇ L/min, the coagulation liquid is absolute ethanol, and then the collected microspheres are washed repeatedly with ethanol to neutrality, and the precipitate is filtered off by suction;
- step 4 Dissolve the product of step 3 in deionized water containing 12g sodium hydroxide, 180g urea and 2000ml at a temperature of -12°C. After the cellulose is fully dissolved, filter it, and spray the filtrate into the coagulation liquid by electrostatic spraying. , The voltage in the electrostatic spraying is 20kV, the feeding rate is 150 ⁇ L/min, the coagulation liquid is absolute ethanol, and then the collected microspheres are washed repeatedly with ethanol until they are neutral for use;
- the product is subjected to 6 hammer milling treatments, and then the product is freeze-dried.
- the dried product is passed through a 100-mesh sieve (to remove particles larger than 150 ⁇ m) and a 300-mesh sieve (to remove particles smaller than 50 ⁇ m), 25kGy Sterilized by irradiation to obtain oxidized cellulose hemostatic powder (microspheres).
- step 4 Dissolve the product of step 3 in deionized water containing 15g of sodium hydroxide, 250g of urea and 2000ml at a temperature of -15°C. After the cellulose is fully dissolved, filter, and spray the filtrate into the coagulation liquid by electrostatic spraying. , The voltage in the electrostatic spraying is 40kV, the feed rate is 100 ⁇ L/min, the coagulation liquid is absolute ethanol, and then the collected microspheres are washed repeatedly with ethanol until they are neutral for use;
- the product is subjected to 4 ball milling treatments with a ball mill, and then spray-dried.
- the dried product is passed through a 100-mesh sieve (to remove particles larger than 150 ⁇ m) and a 300-mesh sieve (to remove particles smaller than 50 ⁇ m), 25kGy radiation According to sterilization, oxidized cellulose hemostatic powder (microspheres) is obtained.
- step 4 Dissolve the product of step 3 in deionized water containing 10g of sodium hydroxide, 20g of urea and 200ml of deionized water at a temperature of -12°C. After the cellulose is fully dissolved, filter, and spray the filtrate into the coagulation liquid by electrostatic spraying. In the electrostatic spraying, the voltage is 20kV, the feeding rate is 120 ⁇ L/min, and the coagulation liquid is absolute ethanol. Then the collected microspheres are washed repeatedly with ethanol until they are neutral for use;
- the product is subjected to 5 times of ball milling treatment with a ball mill, and then vacuum dried.
- the dried product is passed through a 100-mesh sieve (to remove particles larger than 150 ⁇ m) and a 300-mesh sieve (to remove particles smaller than 50 ⁇ m), 25kGy radiation According to sterilization, oxidized cellulose hemostatic powder (microspheres) is obtained.
- the degree of polymerization was tested on the hemostatic materials prepared in the above embodiments, and the test method is as follows:
- the test standard is ASTM (Part15D1795-62).
- the specific steps are as follows: add 0.4 g of sample into an Erlenmeyer flask containing 25 mL of distilled water, and after the sample swells, add 25 mL of 1M copper ethylene diamine aqueous solution to it, seal the mouth of the Erlenmeyer flask, and stir for 30 min. After the sample is completely dissolved, the concentration of the sample is 0.8g/100mL. Then accurately transfer 10 mL of the above sample solution to a viscometer with a capillary inner diameter of 0.62 mm, and place it in a digital thermostat water bath, control the temperature at 25 ⁇ 0.5°C, and keep it constant for 15 minutes. Record the time T 1 for the sample solution to flow through the scale at both ends of the capillary. Also record the time T 0 for the solvent to flow through two graduations. Calculate the relative viscosity of the solution according to formula (1).
- T 1 the time for the sample solution to flow through the scale at both ends of the capillary
- T 0 the time for the solvent to flow through the scale at both ends of the capillary.
- the intrinsic viscosity table By looking up the intrinsic viscosity table, find the corresponding [ ⁇ ]C value according to ⁇ r , where C is 0.008 g/mL. That is, the intrinsic viscosity can be obtained, and then the degree of polymerization DP can be calculated by formula (2).
- Example 2 Example 3
- Example 2 Example 3
- Example 4 Particle size ⁇ m 50 ⁇ 150 50 ⁇ 150 50 ⁇ 150 50 ⁇ 150 Percentage content (%) 76 83 98 91
- Percentage refers to the mass percentage of hemostatic materials with a particle size of 50-150 ⁇ m in all hemostatic materials.
- the carboxyl group content of the hemostatic materials prepared in the above embodiments is determined, and the specific test process is as follows:
- the acid-base neutralization titration method was used to determine the carboxyl group content in the hemostatic material.
- V 1 the volume of NaOH consumed by the sample solution to be tested, L;
- V 2 The volume of NaOH consumed by the blank solution, L;
- Example Example 1 Example 2 Example 3 Example 4 Carboxyl content (%) 25 26 28 twenty two Control 1 Control 1-1 Control 1-2 Control 1-3 Control 1-4 Carboxyl content (%) 13 10 14 11 Control 2 Control 2-1 Control 2-2 Control 2-3 Control 2-4 Carboxyl content (%) 20 18 twenty three 15
- control group 1 is the sample without pretreatment and direct oxidation in the corresponding embodiment
- control group 2 is the sample without ultrasonic treatment in the corresponding embodiment.
- a blood coagulation test was performed on the hemostatic materials prepared in the above embodiments, and the specific test process is as follows:
- the whole blood coagulation index BCI (Blood Clotting Index) was used to evaluate its coagulability in vitro.
- Example 1 Example 2
- Example 3 Example 4 Control BCI value 0.22 0.19 0.17 0.21 0.25
- the hemostatic time test is performed on the hemostatic materials prepared in the above embodiments, and the specific test process is as follows:
- the animals needed for the experiment are 150-250g SD rats, which are raised in the experimental environment for one week before the experiment. 10 SD adult rats, half male and half male, were divided into 5 groups, including the Johnson & Johnson control group. The experimental groups were Example 1, Example 2, Example 3, and Example 4.
- the experimental groups were Example 1, Example 2, Example 3, and Example 4.
- 3% pentobarbital sodium anesthetic was injected intraperitoneally to anesthetize it. After successful anesthesia, his limbs were tied to the operating table. Cut it with scissors at a distance of 2 cm from the end of the tail. After the wound bleeds freely for 20 seconds, apply hemostatic powder immediately and cover the entire wound.
- Example 2 Example 3
- Example 4 Control Hemostasis time (s) 79 76 68 73 85
- the dialysis bag is boiled in pure water for 10 minutes and then taken out. 25 dialysis bags are put into the corresponding number of hemostatic materials, and 7mL of newly prepared 3% hydrogen peroxide is added to immerse, after removing air bubbles, clamp the dialysis bag. Add 7 mL of freshly prepared 3% hydrogen peroxide solution to the remaining 5 dialysis bags as a blank control.
- the above materials were placed in 30 250mL beakers according to their numbers, and 120mL of newly prepared 3% hydrogen peroxide solution was added. The mouth of the beaker was sealed and placed in a shaking incubator. The temperature was set to 37°C, the speed was 150rpm, and the temperature was kept for 14 days. At the same time, replace 100 mL of the newly prepared 3% hydrogen peroxide solution outside the dialysis bag every 24 hours.
- W weight loss percentage, %
- W t The dry weight of the hemostatic material at the specified time point, g.
- Example 1 Example 2
- Example 3 Example 4 Control example 2d 62 54 70 66 43 4d 80 83 92 85 75 6d 98 94 99 96 84 8d 97 97 98 98 96 14d 99 98 99 99 98
- the hemostatic material provided by the present invention has a relatively short in vitro degradation time, which can effectively reduce the possibility of a series of immune reactions such as rejection and wrapping.
- the cytotoxicity test was carried out on the hemostatic materials and instant yarns prepared in the above embodiments.
- the specific test process is as follows:
- Preparation of the extract Under aseptic conditions, accurately weigh the hemostatic material and instant yarn of the same quality of the example, add 50.00mg/mL serum and L-glutamine-free MEM medium at 37°C, Leaching in a constant temperature shaker at 100rpm for 24h. Centrifuge, take the upper layer liquid as the 100% leaching solution, and dilute sequentially to obtain 50%, 25%, and 12.5% material leaching solution. Before adding samples, each extract is supplemented with fetal bovine serum at 10% and L-glutamine at 1% to obtain.
- the extract is tested in accordance with the MTT method specified in GB/T 16886.5-2017.
- the test is based on the relative cell proliferation rate as a criterion.
- the specific test results are shown in Table 7.
- Example 2 Example 3
- Example 4 Control group Original solution (100%) ⁇ 70% ⁇ 70% ⁇ 70% ⁇ 70% ⁇ 70% 50% extract ⁇ 70% ⁇ 70% ⁇ 70% ⁇ 70% 25% extract ⁇ 70% ⁇ 70% ⁇ 70% ⁇ 70% 12.5% extract ⁇ 70% ⁇ 70% ⁇ 70% ⁇ 70% ⁇ 70% ⁇ 70%
- the present invention selects mechanical method to pretreat the cellulose raw material, which improves the accessibility of the cellulose active group hydroxyl group, and then swells it with alkali to further facilitate oxidation.
- the cellulose is oxidized in different ways Treatment, the oxidation process assisted ultrasonic treatment is beneficial to increase the carboxyl content of the oxidation product, and then the coagulant is added to the oxidation product, which is conducive to the coagulation of the hemostatic material, and then the product is shaped by different physical methods.
- the hemostatic material prepared by the above method It has the advantages of fast hemostasis, strong adhesion, good degradability, wide application range, simple operation and low cost.
- the invention provides a novel degradable hemostatic material and a preparation method thereof.
- the hemostatic material of the present invention is oxidized cellulose loaded with clotting factors, wherein the carboxyl content of the oxidized cellulose is 20-30%, the degree of polymerization is 200-400, the particle size is 50-150 ⁇ m, and the clotting factor accounts for the oxidized cellulose. 0.01 to 2% of the mass percentage.
- the preparation method of the present invention includes the steps of oxidation pretreatment process, oxidation process, complexation of blood coagulation factors, electrostatic spraying and molding.
- the invention has the advantages of continuous process, high efficiency, low cost, etc., and prepares an oxidized cellulose hemostatic material with uniform and controllable microspheres, high oxidation degree and strong hemostatic ability.
- the new hemostatic material is suitable for massive hemorrhage, irregular parts and organ hemorrhage.
- the material has good degradability, fast hemostasis, and has good economic value and application prospects.
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Abstract
Description
实施例1 | 实施例2 | 实施例3 | 实施例4 | |
聚合度 | 320 | 280 | 390 | 370 |
实施例1 | 实施例2 | 实施例3 | 实施例4 | |
粒径μm | 50~150 | 50~150 | 50~150 | 50~150 |
百分含量(%) | 76 | 83 | 98 | 91 |
实施例 | 实施例1 | 实施例2 | 实施例3 | 实施例4 |
羧基含量(%) | 25 | 26 | 28 | 22 |
对照1 | 对照1-1 | 对照1-2 | 对照1-3 | 对照1-4 |
羧基含量(%) | 13 | 10 | 14 | 11 |
对照2 | 对照2-1 | 对照2-2 | 对照2-3 | 对照2-4 |
羧基含量(%) | 20 | 18 | 23 | 15 |
实施例1 | 实施例2 | 实施例3 | 实施例4 | 对照 | |
BCI值 | 0.22 | 0.19 | 0.17 | 0.21 | 0.25 |
实施例1 | 实施例2 | 实施例3 | 实施例4 | 对照 | |
止血时间(s) | 79 | 76 | 68 | 73 | 85 |
失重百分率 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 对照例 |
2d | 62 | 54 | 70 | 66 | 43 |
4d | 80 | 83 | 92 | 85 | 75 |
6d | 98 | 94 | 99 | 96 | 84 |
8d | 97 | 97 | 98 | 98 | 96 |
14d | 99 | 98 | 99 | 99 | 98 |
实施倍数 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 对照组 |
原液(100%) | <70% | <70% | <70% | <70% | <70% |
50%浸提液 | ≥70% | ≥70% | ≥70% | ≥70% | <70% |
25%浸提液 | ≥70% | ≥70% | ≥70% | ≥70% | ≥70% |
12.5%浸提液 | ≥70% | ≥70% | ≥70% | ≥70% | ≥70% |
Claims (10)
- 一种新型可降解的止血材料,其特征在于,所述止血材料为负载有凝血因子的氧化纤维素,其中所述氧化纤维素的羧基含量为20~30%,聚合度为200~400,粒径大小为50~150μm,所述凝血因子占所述氧化纤维素质量百分数的0.01~2%。
- 根据权利要求1所述的止血材料,其特征在于,所述凝血因子为可溶性钙盐。
- 权利要求1或2所述止血材料的制备方法,其特征在于,包括以下步骤:A、将纤维素依次经过破碎处理和氢氧化钠溶液润胀处理,制备纤维素;B、对纤维素分子的C 6位羟基进行选择性氧化,在C 6位上引入羧基,得到氧化纤维素;并在氧化过程中辅以超声处理;C、将氧化纤维素与凝血因子按不同条件进行络合;D、将步骤C所得混合物溶于碱体系中,搅拌过滤,收集滤液,将滤液以静电喷射的方式喷射于凝固液中,收集沉淀,用水和/或乙醇洗涤至中性;E、将步骤D所得产物进行机械破碎或研磨,干燥后,过筛,灭菌,即得;其中,步骤D所用凝固液为乙醇、硫酸溶液或盐酸溶液。
- 根据权利要求3所述的方法,其特征在于,步骤A包括:将一定量的纤维素加入到高压均质机、磨浆机、疏解机、粉碎机或超声机中,进行粉碎处理,至纤维长度小于1mm;将浆液过滤,得沉淀物,水洗后,放入1~20%的氢氧化钠溶液中润胀处理20~120min,将润胀后的纤维素用水和/或乙醇洗涤至中性。
- 根据权利要求3所述的方法,其特征在于,步骤B包括:将纤维素加入到氧化体系中进行氧化反应,氧化反应和超声处理同步进行;反应 结束后,过滤或离心收集沉淀,用水和/或乙醇洗涤至中性,得到氧化纤维素;其中,所述氧化体系为NO 2氧化体系、次氯酸盐氧化体系、TEMPO氧化体系或HNO 3/H 3PO 4~NaNO 2氧化体系;所述NO 2氧化体系是以CCl 4为溶剂,配制的浓度为10~30%的NO 2氧化液;所述次氯酸盐氧化体系为20~200%v/v的NaClO溶液;所述TEMPO氧化体系为TEMPO-NaClO-NaBr氧化体系;所述HNO 3/H 3PO 4~NaNO 2氧化体系为含NaNO 2的HNO 3和H 3PO 4混合液。
- 根据权利要求5所述的方法,其特征在于,当所述氧化体系为NO 2氧化体系时,所述步骤B包括:将1~20g纤维素加入到100~200mL所述NO 2氧化体系中,反应温度为5~30℃,反应时间为8~100h;氧化反应和超声处理同步进行;反应结束后,过滤或离心收集沉淀,依次用CCl 4、乙醇洗涤沉淀,得到氧化纤维素;当所述氧化体系为次氯酸盐氧化体系时,所述步骤B包括:将5~20g纤维素悬浮于100~200mL水中,调悬浮液pH至9~11,在40~60℃条件下,向其中加入20~100%v/v的NaClO溶液20~200mL,反应2~10h;氧化反应和超声处理同步进行;反应结束后,过滤或离心收集沉淀,用水和/或乙醇洗涤至中性,得到氧化纤维素;当所述氧化体系为TEMPO氧化体系时,所述步骤B包括:将10~100g纤维素悬浮于pH9~11的Na 2CO 3/NaHCO 3缓冲液100~1000mL中,搅拌2~10min后,加入TEMPO,使TEMPO的终浓度为0.1~1.0mg/mL,再加入NaBr,使NaBr的终浓度为1~10mg/mL;控制反应体系温度为20~30℃,待TEMPO和NaBr完全溶解后,调反应体系pH至9~11,然后分步加入饱和NaClO溶液,每隔30~60min加一次,NaClO溶液加入的体积为溶液总体积的20~100%,反应3~10h;氧化反应和超声处理同步进行;反应 结束后,过滤或离心收集沉淀,用水和/或乙醇洗涤至中性,得到氧化纤维素;其中,所述Na 2CO 3/NaHCO 3缓冲液中Na 2CO 3和NaHCO 3的摩尔比为1:3~3:1;当所述氧化体系为HNO 3/H 3PO 4~NaNO 2氧化体系时,所述步骤B包括:将HNO 3和H 3PO 4分析纯按体积比0.5:1~3:1配制成混合液,将纤维素加入到上述混合液中,使其浓度为0.01~0.1g/mL,再加入NaNO 2粉末,使NaNO 2的终浓度为10~50mg/mL;在20~50℃条件下反应8~48h;氧化反应和超声处理同步进行;反应结束后,过滤或离心收集沉淀,用水和/或乙醇洗涤至中性,得到氧化纤维素。
- 根据权利要求3所述的方法,其特征在于,步骤B中超声条件为:超声频率20~40kHz,功率100~1000W。
- 根据权利要求3所述的方法,其特征在于,所述步骤D中,将步骤C所得混合物在-20~-5℃条件下溶于碱体系中;所述碱体系为5~20%氢氧化钠溶液、含5~30%尿素的5~20%氢氧化钠溶液或含5~30%尿素的5~20%氢氧化锂溶液。
- 根据权利要求3所述的方法,其特征在于,所述步骤D中,静电喷射的电压为5~20kV,供料速率为20~400μL/min。
- 根据权利要求3-9中任一项所述的方法,其特征在于,步骤E中采用的干燥方式为喷雾干燥、超临界干燥、真空干燥、鼓风干燥或冷冻干燥。
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