CN107737368B - Hemostatic material and its preparation method and application - Google Patents

Hemostatic material and its preparation method and application Download PDF

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Publication number
CN107737368B
CN107737368B CN201711047605.6A CN201711047605A CN107737368B CN 107737368 B CN107737368 B CN 107737368B CN 201711047605 A CN201711047605 A CN 201711047605A CN 107737368 B CN107737368 B CN 107737368B
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nano
hemostatic material
hemostatic
fiber
crosslinking
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CN107737368A (en
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李林静
邓坤学
袁玉宇
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Guangzhou Maple Regenerative Medicine Polytron Technologies Inc
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Guangzhou Maple Regenerative Medicine Polytron Technologies Inc
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Priority to PCT/CN2018/095636 priority patent/WO2019011333A1/en
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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
    • A61L24/10—Polypeptides; Proteins
    • A61L24/104—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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • 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
    • 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
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • 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
    • 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
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • 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
    • A61L24/10—Polypeptides; Proteins
    • A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
    • 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
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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

Abstract

The present invention provides a kind of hemostatic material and its preparation method and application.The hemostatic material includes nano-fibre cluster, and nano-fibre cluster is derived from the nano-fiber material of crosslinking, nano-fibre cluster using its geometric center as starting point towards three-dimensional space any direction size in 5 μm~500 μ ms；And/or in hemostatic material nano-fibre cluster with median D50The size of expression is between 100 μm -500 μm；Nano-fibre cluster has porous structure, and nano-fibre cluster has the cross structure that formation is mutually overlapped by more nano short fibers；The diameter of nano short fiber is between 1nm~1000nm, and length is at 1000 μm or less；The porosity of hemostatic material is 50%~90%.Hemostatic material of the invention has excellent tissue adhension performance and significant haemostatic effect, excellent tissue adherence can guarantee that material fits closely in hemostasis with the surface of a wound, it prevents from being washed away by blood, significantly improves haemostatic effect, and promote its mutual fusion process with tissue.

Description

Hemostatic material and its preparation method and application
Technical field
The present invention relates to a kind of hemostatic materials and its preparation method and application, belong to biomedical materials field.
Background technique
Bio-medical material is a kind of new and high technology material to grow up in the late three decades, wherein hemostatic material also with The accidents such as traffic accident, serious burn and scald and disaster increase the concern for gradually causing medical field.With modern section The high speed development of technology, the research of hemostatic material achieve very fast progress, and various novel hemostatic materials continuously emerge, property Very big promotion can also have been obtained.Currently, common topical hemostatic agent has Fibrin Glue, thrombin powder, gelfoam, collagen Protein sponge, chitosan sponge, oxycellulose, microfibrillar collagen, alginic acid fibre, zeolite, cyanoacrylate, plant are more Icing Sugar etc..Haemostatic effect is definite, easy to use, good biocompatibility, can control the bio-medical hemostatic material of degradation rate at The main object paid close attention to and studied for people.
The form of common hemostatic material includes diversified forms, there is powdery, as fibrin ferment freeze-dried powder, plant polyose powder, Zeolite powder, microfibrillar collagen powder；There is solution-type, such as cyanoacrylate, chitosan solution；There is liquid-type, but in surface of a wound energy shape At gel or colloid, such as Fibrin Glue, glutaraldehyde-albumin Bioglue；Have it is membranaceous, such as chitosan film, polylactic acid membrane；Also Have it is spongy, such as collagen protein sponge, gelfoam, microfibrillar collagen sponge, fibrin patch.The hemostatic material of various forms Material respectively has its advantage, also has respective application advantage, is mainly selected according to surface of a wound type and clinical treatment mode.
In the prior art, the hemostatic material of powdery is mainly polysaccharide microsphere or starch granules, passes through supercritical ultrasonics technology, wet heating The technologies such as processing, microwave method, Mechanical Method or enzyme perforation realize more microporous of material surface, promoted material specific surface area and Hydrophilicity plays molecular sieve in wound surface, and the concentration of coagulation factor is promoted by the moisture in absorption blood, is added The generation of fast clotting mechanism, to realize anastalsis.But there are poor adhesions for current styptic powder, relatively closely knit, preparation The problems such as complex process, and need to prepare in advance, waste the time of many rescue hemostasis.
Summary of the invention
Problems to be solved by the invention
The purpose of the present invention is to provide a kind of hemostatic materials, with high-specific surface area, excellent adhesion property and show The haemostatic effect of work.
Further, hemostatic material of the invention also has high porosity, high water absorbing capacity and good biocompatibility, And it can rapidly be degraded and absorb by organism.
The solution to the problem
The present invention provides a kind of hemostatic material, and the hemostatic material includes nano-fibre cluster, and the nano-fibre cluster is originated from In the nano-fiber material of crosslinking,
The nano-fibre cluster using its geometric center as starting point towards three-dimensional space any direction size in 5 μm~500 μ Within the scope of m；And/or in the hemostatic material nano-fibre cluster with median D50The size of expression 100 μm -500 μm it Between, preferably between 200 μm -400 μm；
The nano-fibre cluster has porous structure, and the nano-fibre cluster has by more nano short fiber phase interconnections Connect the cross structure to be formed；The diameter of the nano short fiber is between 1nm~1000nm, and length is at 1000 μm or less；
The porosity of the hemostatic material is 50%~90%, preferably 70%~90%.
Hemostatic material according to the present invention, the specific surface area of the hemostatic material are 4m2/ g~50m2/ g, preferably 10m2/ G~40m2/g。
The heap density of hemostatic material according to the present invention, the hemostatic material is less than 0.06g/cm3, preferably 0.025g/ cm3~0.05g/cm3。
Hemostatic material according to the present invention, the water absorption rate of the hemostatic material are greater than 1500%, preferably 2000%~ Water absorption rate between 3000%.
Hemostatic material according to the present invention, the nano-fiber material be originated from biocompatibility and can organism drop The polymer material absorbed is solved, the nano-fiber material is interwoven by fiber filament；Preferably, the nano-fiber material is Coma, fibre bundle or tunica fibrosa.
Hemostatic material according to the present invention, the crosslinking are crosslinking in the presence of crosslinking agent, it is preferable that the crosslinking agent Mass ratio with the nano-fiber material is 0.01~2:1, preferably 0.1~1:1.
Hemostatic material according to the present invention, the hemostatic material also include drug；Preferably, the drug includes blood coagulation The combination of one or more of enzyme, coagulation factor, growth factor.
The present invention provides a kind of preparation method of hemostatic material according to the present invention, comprising the following steps:
Electrostatic spinning step: the nano-fiber material is prepared by electrostatic spinning；
Cross-linking step: crosslinking Treatment is carried out to the nano-fiber material in the presence of a crosslinking agent, what is be crosslinked receives Rice fibrous material；
It shears step: shear treatment being carried out to the nano-fiber material of the crosslinking, obtains formed body；
Sifting step: sieving processing is carried out to the formed body.
The preparation method of hemostatic material according to the present invention, the crosslinking agent include: carbodiimides, N- hydroxysuccinimidyl acyl The combination of one or more of imines, Geniposide or aldehyde compound,
Preferably, the crosslinking agent includes carbodiimides and n-hydroxysuccinimide, it is highly preferred that the carbonization two The mass ratio of imines and n-hydroxysuccinimide is 1~4:1.
The preparation method of hemostatic material according to the present invention, the shear treatment include,
Pre- shearing step carries out the nano-fiber material of the crosslinking under the revolving speed of 10000~20000rpm/min Preliminary shear treatment obtains pre- cutting object, and/or
High speed shear step carries out high speed shear to the pre- cutting object under the revolving speed of 30000~50000rpm/min Processing.
The preparation method of hemostatic material according to the present invention, the sieving processing are to carry out sieving using the mesh screen of 18 mesh, Collect the formed body that sieving passes through.
The preparation method of hemostatic material according to the present invention, the preparation method further include,
Step is sheared again: under the revolving speed of 40000~50000rpm/min, the unsanctioned formed body of sieving being carried out again Secondary shear treatment.
The preparation method of hemostatic material according to the present invention, the shear treatment be in the state of being passed through flowing gas into Capable.
The preparation method of hemostatic material according to the present invention, between the cross-linking step and shearing step further include: elution Step and/or freeze-drying step.
The present invention also provides a kind of hemostatic articles, comprising: hemostatic material according to the present invention or hemostatic material of the invention The hemostatic material that the preparation method of material is prepared.
The effect of invention
Hemostatic material of the invention has excellent tissue adhension performance and significant haemostatic effect, excellent tissue adhension Performance enough guarantees that material fits closely in hemostasis with the surface of a wound, prevents from being washed away by blood, significantly improves haemostatic effect, and promote Into the mutual fusion process of itself and tissue.
Further, since hemostatic material has high-specific surface area and high porosity, so as in blood environment The moisture in blood can be absorbed rapidly, improved effective blood coagulation factor concentration in blood, started the endogenous and external source of body Property hemostatic mechanism, accelerate the generation of coagulation process, thus realize quick-acting haemostatic powder act on.
Further, hemostatic material of the invention also has good biological property, not only has good bio-compatible Property, can rapidly be degraded by organism absorbs, and clinical use is convenient, can be used for stopping in trauma care and clinical operation Blood.
Detailed description of the invention
Fig. 1 is the SEM Electronic Speculum schematic diagram of nano-fibre cluster in the hemostatic material of the embodiment of the present invention 1.
Fig. 2 is the hemostatic material of the embodiment of the present invention 1 and the hemostasis validity comparison diagram of commercial product 1.
Fig. 3 is that the hemostatic material of the embodiment of the present invention 1 is degraded pathology figure in animal body.
Fig. 4 is that commercial product 1 is degraded pathology figure in animal body.
Specific embodiment
Various exemplary embodiments, feature and the aspect of the disclosure are described in detail below with reference to attached drawing.It is dedicated herein Word " exemplary " mean " be used as example, embodiment or illustrative ".Here as any embodiment illustrated by " exemplary " It should not necessarily be construed as preferred or advantageous over other embodiments.
In addition, giving numerous details in specific embodiment below in order to which the disclosure is better described. It will be appreciated by those skilled in the art that without certain details, the disclosure equally be can be implemented.In other example, Method well known to those skilled in the art, means, equipment and step are not described in detail, in order to highlight the master of the disclosure Purport.
First embodiment
First embodiment of the invention provides a kind of hemostatic material.The hemostatic material includes nano-fibre cluster, described Nano-fibre cluster has the cross structure that formation is mutually overlapped by more nano short fibers；The nano-fibre cluster is derived from crosslinking Nano-fiber material.
Wherein, the nano-fiber material of crosslinking can be obtained by carrying out cross-linking modified processing to nano-fiber material.
Hemostatic material can be by being sheared to obtain to the nano-fiber material being crosslinked.It is clipped while can be formed and receive Rice staple fiber, so that nano-fibre cluster has the cross structure by the more mutual overlap to form of nano short fiber.
The hemostatic material that present embodiment provides macroscopically is being powdery or graininess, can be by spraying or spraying Mode is applied on the surface of a wound, and the lacuna type surface of a wound or the narrow surface of a wound are particularly suitable for.
<nano-fiber material>
Nano-fiber material of the invention can be originated from biocompatibility and can organism degradation absorb polymerization Object material, the more preferably polymer material of good hydrophilic property.For example, polymer material may include collagen (Collagen), one of chitosan (Chitosan), hyaluronic acid (HA), alginate, cellulose and its derivates or Two or more combinations.
Nano-fiber material of the invention can be interwoven by fiber filament.Preferably prepared using electrospinning process Nano-fiber material.The nano-fiber material can be coma, fibre bundle or tunica fibrosa, preferably tunica fibrosa.
The principle of electrostatic spinning is to apply high voltage during electrostatic spinning to polymeric liquid, charge is made to introduce liquid Body.When the accumulation in liquid to it is a certain amount of when, liquid can spray head formed taylor cone, in the effect of extra electric field power Under overcome surface tension formed liquid jet, then jet stream is in the common of electrostatic repulsion, Coulomb force (Coulomb) and surface tension Under effect, polymer jet stream is moved along random coil shape track.Jet stream is stretched by traction in a very short period of time, as solvent is waved Hair or heat loss, polymer jet stream are formed by curing micrometer/nanometer fiber.During electrostatic spinning, many parameters can be to most Whole electrospun fibers have an impact, and by control process parameter, can prepare different sizes, form and different structure Micrometer/nanometer fiber.
During electrostatic spinning of the invention, technological parameter can generate shadow to the nano-fiber material that electrostatic spinning obtains It rings, by controlling technological parameter, the nano-fiber material of different sizes, form and different structure can be prepared.The present invention The mode of electrostatic spinning is not required particularly, can be electrostatic spinning mode commonly used in the art.Specifically, this Polymer material is dissolved in suitable solvent by invention, prepares the spinning solution of polymer material；Then use electrostatic spinning will Spinning solution is spun into the nano-fiber material being interwoven by fiber filament.Preferably, the nano-fiber material has porous Structure.
<nano-fiber material of crosslinking>
The nano-fiber material of crosslinking of the invention can be obtained by carrying out cross-linking modified processing to nano-fiber material. Specifically, cross-linking modified is cross-linking modified in the presence of crosslinking agent, so that it is suitable and uniform to obtain the degree of cross linking It is crosslinked.
In the present invention, carry out cross-linking modified purpose be in order to make hemostatic material while a large amount of imbibitions, can be very Good maintenance fibre morphology, the body fluid that will not be absorbed soon are dissolved or are broken up.In addition, since the excessively high degree of cross linking can shadow Water absorption rate, flexibility etc. are rung, in order to obtain the more suitable degree of cross linking, the mass ratio of crosslinking agent and nano-fiber material in the present invention For 0.01~2:1, preferably 0.1~1:1.
<nano short fiber>
The diameter of nano short fiber of the invention is between 1nm~1000nm, and length is generally in 10mm hereinafter, can be 8mm is hereinafter, can be in 5mm or less.In general, nanofiber in the narrow sense is Nanowire of the diameter within the scope of 1~100nm Dimension, sensu lato nanofiber further includes that nano-composite fiber, i.e. zero dimension or monodimension nanometer material are combined with conventional fibre Traditional fibre.For polymer nanocomposite material fiber, due to its just produced on the scale of 1000nm it is many special Performance, such as huge surface area, easy surface-functionalized and superior mechanical performance, therefore nanofiber refers to directly in the present invention Nanofiber of the diameter within the scope of 1~1000nm.
<nano-fibre cluster>
As shown in Figure 1, nano-fibre cluster of the invention has porous structure.Nano-fibre cluster can be by receiving to what is be crosslinked Rice fibrous material is sheared to obtain.It is clipped to be formed simultaneously nano short fiber, so that nano-fibre cluster has by more nanometers The cross structure of formation is mutually overlapped between staple fiber.Due to mutually overlapping the cross structure of formation between more nano short fibers And the size of nano-fibre cluster is smaller, so that nano-fibre cluster is in fluffy state, so as to increase nano-fibre cluster Specific surface area.
The nano-fibre cluster using its geometric center as starting point towards three-dimensional space any direction size in 5 μm~500 μ Within the scope of m；Specifically, the nano-fibre cluster can be with by the size of starting point towards three-dimensional space any direction of its geometric center Between 5 μm~50 μm, can between 5 μm~100 μm, can between 5 μm~200 μm, can 5 μm~250 μm it Between, can between 5 μm~300 μm, can between 5 μm~350 μm, can between 5 μm~400 μm, can 5 μm~ It, can be between 5 μm~500 μm between 450 μm.
<hemostatic material>
As shown in Figure 1, the hemostatic material includes nano-fibre cluster.Nano-fibre cluster with median in hemostatic material D50The size of expression is between 100 μm -500 μm, preferably between 200 μm -400 μm.Median D described herein50I.e. Nano-fibre cluster cumulative particle sizes percentile in hemostatic material reaches partial size corresponding when 50%.
The heap density of the hemostatic material is less than 0.06g/cm3, preferably 0.025g/cm3~0.05g/cm3.Hemostatic material Heap density it is small, with high loft characteristic and superelevation specific surface area.The porosity of the hemostatic material be 50%~ 90%, preferably 70%~90%.The specific surface area of the hemostatic material is 4m2/ g~50m2/ g, preferably 10m2/ g~40m2/ g.The water absorption rate of the hemostatic material is greater than 1500%, and the water absorption rate preferably between 2000%~3000% has high water absorption Performance.
The heap density having due to state hemostatic material of the invention is small, specific surface area is high, porosity is high and water absorption rate is high Characteristic can be further improved red blood cell in blood, blood coagulation so as to absorb the moisture in blood rapidly in the bleeding surface of a wound The concentration of the factor etc. accelerates intrinsic coagulation mechanism, improves haemostatic effect.
Further, hemostatic material of the invention also includes drug.Preferably, the drug includes fibrin ferment, blood coagulation The combination of one or more of the factor, growth factor.By loading drug, the hemostasis of hemostatic material not only can be improved Performance is also provided simultaneously with and the performances such as promotes quick healing of cut, prevents adhesion.
Second embodiment
Second embodiment of the present invention provides a kind of preparation method of hemostatic material, comprising the following steps:
Electrostatic spinning step: the nano-fiber material is prepared by electrostatic spinning；
Cross-linking step: crosslinking Treatment is carried out to the nano-fiber material in the presence of a crosslinking agent, what is be crosslinked receives Rice fibrous material；
It shears step: shear treatment is carried out to the nano-fiber material of the crosslinking；
Sifting step: sieving processing is carried out to the formed body.
Described herein is " crosslinking " and " cross-linking modified " with the same or similar meaning, during " crosslinking ", It can be accompanied with the Some features of " modification ", in the present invention for simplicity, " crosslinking " replacement " cross-linking modified " can be used.
<electrostatic spinning step>
In the electrostatic spinning step, fibrous raw material is prepared in advance, fibrous raw material is dissolved in suitable solvent, is prepared into The spinning solution of certain density fibrous raw material.Wherein, the fibrous raw material can be the polymeric material in first embodiment Material.For the specific concentration of solvent type that forms solution, there is no particular limitation, as long as can satisfy subsequent electrostatic spinning work The requirement of skill.For example, suitable solvent can be trifluoroethanol, hexafluoroisopropanol, trifluoroacetic acid, cyclohexanone, third The combination of one or more of ketone, butanone, tetrahydrofuran, chloroform, glacial acetic acid, formic acid, propionic acid or water.
Nano-fiber material needed for adjusting spinning parameter preparation can be passed through during electrostatic spinning.Such as voltage, squeeze Outflow and electric field reception distance, spinning environment etc..Preferably, heretofore described electrostatic spinning process parameter can be with are as follows: pressure Power is 10~40kV, and it is 0.1~15mL/h that solution, which squeezes out flow, and electric field reception distance is 5~30cm, spinning environment relative temperature 60% hereinafter, environment temperature is 10~40 DEG C.
Furthermore it is possible to consider to load drug in spinning solution or in electro-spinning process, the drug may include blood coagulation The combination of one or both of the factor, growth factor etc..The anthemorrhagic performance of material not only can be improved, be also provided simultaneously with promotion Wound healing, the performances such as prevent adhesion.
<cross-linking step>
In the cross-linking step, selected crosslinking agent include carbodiimides, n-hydroxysuccinimide, Geniposide, The combination of one or more of aldehyde compound.
In view of crosslinking agent is to organismal toxicity size and cross-linking effect, crosslinking agent can select carbodiimides and/or N-hydroxysuccinimide.It is according to the invention the study found that can be further improved by using n-hydroxysuccinimide The cross-linking effect of carbodiimides.Therefore, chemical cross-linking agent is preferably the combination of carbodiimides and n-hydroxysuccinimide. The mass ratio of the more preferably described carbodiimides and n-hydroxysuccinimide is 1~4:1.
In general, cross-linking modified carry out in the solution, in the present invention not to the solvent of the cross-linking modified processing of progress It is specifically limited, as long as can satisfy the demand of cross-linking modified reaction.In the present invention, the molten of cross-linking modified processing is carried out Agent can be the alcohol of different quality ratio and the mixed solution of water.Wherein, alcohol is preferably ethyl alcohol, it is highly preferred that the matter of ethyl alcohol and water Ratio is measured 70% or more.
It is cross-linking modified to control it is possible to further the dosage of reaction condition, crosslinking agent by adjusting crosslinking Treatment The case where.Such as crosslinking Treatment temperature, the crosslinking Treatment time, the mass ratio of crosslinking agent and nano-fiber material, crosslinking agent matter The ratio between amount and the volume of solvent etc..Furthermore it is possible to by regulation crosslinking degree, to meet different wounds or clinical operation to drop Solve the requirement in period.
Reaction condition in heretofore described cross-linking step can be, and crosslinking Treatment temperature is between 1~50 DEG C, preferably Between 4~30 DEG C.The crosslinking Treatment time between 1~72h, preferably 6~for 24 hours between.The quality of the chemical cross-linking agent Mass ratio with nano-fiber material is 0.01~2:1, preferably 0.1~1:1.The quality of chemical cross-linking agent and the volume of solvent it Than for 0.1~10:100, wherein it is preferred that 1~5:100.Crosslinking degree can be further controlled by controlling above-mentioned reaction condition.
In addition, in the present invention, crosslinking Treatment first can also be carried out to fibrous raw material, then again using electrostatic spinning technique into Row processing, is preferably first handled using electrostatic spinning technique, then carries out crosslinking Treatment to nano-fiber material.
<shearing step>
In shearing step of the invention, the shear treatment may include pre- shearing step, specifically, the pre- shearing step Rapid is to carry out preliminary shear treatment to the nano-fiber material of the crosslinking under the revolving speed of 10000~20000rpm/min, is obtained To pre- cutting object.In general, the processing time of shearing step is 10~60min, preferably 20~30min in advance.By shearing in advance Processing, cross-linking system can tentatively be shredded obtain uniform platelet-shaped material.
Further, the shear treatment also may include high speed shear step, in the high speed shear step, in order to most The hemostatic material obtained eventually forms more uniform form, and the revolving speed of high speed shear step and time are more crucial；Specifically, high speed The revolving speed for shearing step can be in 30000~50000rpm/min, preferably between 30000~40000rpm/min；High speed is cut The time for cutting step is 10~30min, more preferably 15~20min.
Further, the shear treatment is carried out in the state of being passed through flowing gas.Specifically, the shearing Processing carries out in a reservoir, and has been passed through flowing gas in the container.The container can be closed or non-closed 's.For example, shear treatment of the invention, which can be, is handled using specific cutter.Cutter can have use In the container for the nano-fiber material for holding the crosslinking.It can be passed through flowing gas in a reservoir, and then to the crosslinking Nano-fiber material is sheared.In the nano short fiber obtained after clipped, at least partly nano short fiber mutually overlaps shape At nano-fibre cluster, and what nano-fibre cluster can be fluffy is distributed in the inner space of the container.
Preferably, cutter of the present invention can be passed through flowing gas by way of inflation into container.It can be continuous Inflation is also possible to interval and inflates, and can also be the mode of circulation inflatable.Flowing gas in the present invention can be to form convection current Gas, or form the gas etc. of disturbance.
The material of container of the invention is preferably non-metallic material, such as: the non-metallic materials such as organic glass, tetrafluoroethene Matter.This is because container is connected to the motor during high speed shear, metal material is easy thermally conductive, and high temperature is easy to make nanofiber Dissolution denaturation occurs for cluster, to influence the performance of nano-fibre cluster to a certain extent, and then influences the performance of hemostatic material.Cause This, selects non-metallic material, can be to avoid the performance for influencing hemostatic material.In addition, for the ease of observing shear effect, preferably Organic glass material.
Due to being passed through flowing gas in shear history, that shears is more uniform, and can be further such that only Blood material obtains higher fluffy degree, to further increase the specific surface area of hemostatic material.
<sifting step shears step again>
In sifting step in the present invention, sieving processing collects what sieving passed through to carry out sieving using the mesh screen of 18 mesh Formed body.It to obtaining the suitable nano-fibre cluster of size, i.e., is starting point towards three-dimensional space using the geometric center of nano-fibre cluster Between any direction size in 5 μm~500 μ ms.
Preparation method of the invention further includes shearing step again；The step of shearing again be 40000~ Under the revolving speed of 50000rpm/min, shear treatment again is carried out to the unsanctioned formed body of sieving.It is suitable further to obtain size Nano-fibre cluster.Preferably, the time of the shear treatment again is 1~30min, preferably 10~20min.
<elution step, freeze-drying step>
It can also include: elution step and/or freeze-drying step between the cross-linking step and shearing step.
The purpose eluted is the unreacted crosslinking agent of removal.Specifically, the elution step may include: 0~ Eluant, eluent is utilized in a low temperature of 20 DEG C, and the nano-fiber material being crosslinked is eluted by E-test, it is described not with removal The crosslinking agent of reaction.The eluant, eluent includes the mixed liquor of alcohols and water, preferably includes the mixed liquor of second alcohol and water, more preferably Ground, the mass fraction of ethyl alcohol is 70% or more in the mixed liquor of second alcohol and water.In addition, eluant, eluent and crosslinking Treatment in the present invention Employed in solvent may be the same or different.
Further, the alcohol-water solution that can use various concentration in the present invention, is repeatedly washed using E-test It is de-.Preferably, elution requirement are as follows: eluting temperature is 1~20 DEG C, preferably 4~10 DEG C；Elution time be 0.1~5h, preferably 0.5 ~2h is repeated 3~5 times.
The purpose being freeze-dried is the extra solvent and eluant, eluent removed in crosslinking Treatment, is helped to improve simultaneously The porosity of hemostatic material.The freeze-drying the specific steps are, the nano-fiber material after elution is put into container, 1~3h is pre-chilled at -20~-80 DEG C, then container is transferred in freeze drier and is lyophilized, the temperature of freeze-drying is -10 ~40 DEG C, preferably -10~30 DEG C；6~72h of freeze-drying at 1~100pa, preferably 20~40pa vacuum degree, preferably 12~for 24 hours.
By using the hemostatic material that preparation method of the invention is prepared, stop relative to commercially available collagen class microfibre Blood meal, production and processing technology is more simple, and cost is lower, and the selection source of raw material is more extensive, is more in line with industrial metaplasia The requirement of production.
Furthermore it is possible to which the nano-fibre cluster sealed package that will be obtained after shearing, carries out at the sterilizing of Co-60 gamma-ray irradiation Reason.Specifically, the sealed package requires in dry environments, ambient humidity fast packing below 30%；Co-60 gamma-rays Irradiation dose is 15~30kGY.
It need to only be taken out from the package, be can be used to without preparing in advance when use by hemostatic material prepared by the present invention The surface of a wound saves valuable rescue time, facilitates and simplifies operation, while product is carried and saved more easy.
Third embodiment
Third embodiment of the present invention also provides a kind of hemostatic article, comprising: first embodiment according to the present invention The hemostatic material that the preparation method of hemostatic material or the hemostatic material of second embodiment of the present invention is prepared.
Hemostatic article of the invention can be used for when organizing oozing of blood, capillary hemorrhage, parteriole bleeding, lacuna oozing of blood It hemostasis and repairs, and/or, for burning, the hemostasis and reparation of wound, surgical operation wound, have broad application prospects.? It, can be by means of assisting mating instrument to be applied to the portions such as lacuna in the case where applying the hemostasis and reparation in lacuna oozing of blood This product and other commercial product can be rule of thumb combined, such as styptic sponge, hemostatic yarn by the oozing of blood of position or doctor The products such as cloth, to reach better haemostatic effect.
Hemostatic article of the invention forms adhesion energy in wound surface since hemostatic material has good adhesion property The preferable gel of power carries out good physics closure and realizes hemostasis by compression.Simultaneously as having superhigh specific surface area and parent The selection of aqueous polymer material can enable material to have high-hydrophilic.It can be absorbed in blood rapidly in the bleeding surface of a wound Moisture accelerate intrinsic coagulation mechanism to provide the concentration of red blood cell in blood, coagulation factor etc., improve haemostatic effect.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is It can be with conventional products that are commercially available.
Embodiment 1
(1) gelatin (Gelatin) is dissolved in hexafluoroisopropanol, wherein the mass concentration of gelatin is 12% (g/mL), is stirred It mixes dissolution and obtains uniform polymer solution, as spinning solution.The polymer solution is placed in electrostatic spinning syringe, The rate for adjusting micro-injection pump is 6mL/h, and the voltage for adjusting high pressure generator is 25kV, adjusts the reception distance of reception device For 10cm, spinning environment relative humidity is set as 40%, and environment temperature is 30 DEG C, carries out electrostatic spinning, passes through high-voltage electrostatic spinning The nano-fiber material being interwoven by fiber filament and with porous structure is prepared in technology.
(2) in 500mL reactor, 225mL ethanol solution is added, adds 25mL aqueous solution, stirs and evenly mixs, so After weigh 3.57g carbodiimides and 1.43gN- HOSu NHS is dissolved at normal temperature in above-mentioned ethanol-water solution, 5g nano-fiber material is put into reactor, cross-linking modified, processing 12h, the nanofiber material being crosslinked are carried out at 25 DEG C Material.
(3) ethanol-water solution that configuration ethyl alcohol mass fraction is 70%, after a period of time 3h is pre-chilled in a low temperature of 4 DEG C, The nano-fiber material of crosslinking is transferred in the ethanol-water solution that above-mentioned ethyl alcohol mass fraction is 70% and is eluted；Elution After 1h, it is again transferred in 4 DEG C of the ethanol-water solution that ethyl alcohol mass fraction is 95%；After eluting 1h, ethyl alcohol matter is transferred to It is eluted in 4 DEG C of the ethanol-water solution that amount score is 70%, elutes 1h.Eluted using E-test, with removal Unreacted carbodiimides and n-hydroxysuccinimide, are repeated 3 times.
(4) nano-fiber material after elution is put into clean container and 3h is pre-chilled at -80 DEG C, then turn container It moving in freeze drier and is lyophilized, the temperature that freeze-drying is arranged is that 3h is dried at 10 DEG C, it is then dried at 20 DEG C again for 24 hours, Vacuum degree is set as 30pa.
(5) it by the nano-fiber material after freeze-drying, is put into high-speed shearing machine, setting revolving speed is 10000rpm/ Min, processing time are 30min, are tentatively sheared, obtain the pre- cutting object of strip；Then it sets revolving speed to 30000rpm/min after handling 20min to the pre- cutting object high speed shear of strip, carries out sieving using the mesh screen of 18 mesh, receives The formed body that passes through of collection sieving is to get to part nano-fibre cluster.
(6) the larger cluster not by mesh screen is placed again into high-speed shearing machine, setting revolving speed is 40000rpm/min； The processing time is 10min, obtains part nano-fibre cluster.
(7) the nano-fibre cluster sealed package that will be obtained after shearing carries out at the Co-60 gamma-ray irradiation sterilizing of 25kGY After reason, hemostasia products are obtained.The electron microscope of single nano-fibre cluster is as shown in Figure 1 in the hemostasia products.
Embodiment 2
(1) fibroin albumen (Silk Fibroin) is dissolved in formic acid, wherein the mass concentration of fibroin albumen is 10% (g/mL), stirring and dissolving obtains uniform polymer solution, as spinning solution.Polymer solution is placed in electrostatic spinning injection In device, the rate for adjusting micro-injection pump is 2mL/h, and the voltage for adjusting high pressure generator is 30kV, adjusts connecing for reception device Receiving distance is 15cm, and spinning environment relative humidity is set as 30%, and environment temperature is 40 DEG C, carries out electrostatic spinning.It is quiet by high pressure The nano-fiber material being interwoven by fiber filament and with porous structure is prepared in Electrospinning.
(2) in 500mL reactor, 150mL ethanol solution is added, adds 50mL aqueous solution and 4mL glutaraldehyde Stirred and evenly mixed after solution, 2g nano-fiber material be put into reactor, carried out at 40 DEG C it is cross-linking modified, processing for 24 hours, handed over The nano-fiber material of connection.
(3) ethanol-water solution that configuration ethyl alcohol mass fraction is 70%, after a period of time 3h is pre-chilled in a low temperature of 4 DEG C, The nano-fiber material of crosslinking is transferred in the ethanol-water solution that above-mentioned ethyl alcohol mass fraction is 70% and is eluted；Elution After 1h, it is again transferred in 4 DEG C of the ethanol-water solution that ethyl alcohol mass fraction is 95%；After eluting 1h, ethyl alcohol matter is transferred to It measures in 4 DEG C of the ethanol-water solution that score is 70%, elutes 1h.It is eluted using E-test, it is unreacted to remove Glutaraldehyde is repeated 3 times.
(4) nano-fiber material after elution is put into clean container and 3h is pre-chilled at -80 DEG C, then shift container It is lyophilized into freeze drier, the temperature that freeze-drying is arranged is that 3h is dried at -10 DEG C, is then dried for 24 hours, very at 20 DEG C again Reciprocal of duty cycle is set as 20pa.
(5) it by the nano-fiber material after freeze-drying, is put into high-speed shearing machine, setting revolving speed is 15000rpm/ Min, processing time are 20min, are tentatively sheared, obtain the pre- cutting object of strip.Then it sets revolving speed to 40000rpm/min after handling 30min to the pre- cutting object high speed shear of strip, carries out sieving using the mesh screen of 18 mesh, receives The formed body that passes through of collection sieving is to get to part nano-fibre cluster.
(6) the larger cluster not by mesh screen is placed again into high-speed shearing machine, setting revolving speed is 50000rpm/min； The processing time is 10min, obtains part nano-fibre cluster.
(7) the nano-fibre cluster sealed package that will be obtained after shearing carries out at the Co-60 gamma-ray irradiation sterilizing of 25kGY After reason, hemostasia products are obtained.
Embodiment 3
(1) polyvinyl alcohol (PVA) is dissolved in purified water, wherein the mass concentration of polyvinyl alcohol is 5% (g/mL), is stirred It mixes dissolution and obtains uniform polymer solution, as spinning solution.Polymer solution is placed in electrostatic spinning syringe, is adjusted The rate of micro-injection pump is 2mL/h, and the voltage for adjusting high pressure generator is 30kV, and the reception distance for adjusting reception device is 15cm, spinning environment relative humidity are set as 30%, and environment temperature is 40 DEG C, carries out electrostatic spinning.Pass through high-voltage electrostatic spinning skill The nano-fiber material being interwoven by fiber filament and with porous structure is prepared in art.
(2) in 500mL reactor, 150mL ethanol solution is added, adds 50mL aqueous solution and 4mL glutaraldehyde Stirred and evenly mixed after solution, 2g nano-fiber material be put into reactor, carried out at 40 DEG C it is cross-linking modified, processing for 24 hours, handed over The nano-fiber material of connection.
(3) ethanol-water solution that configuration ethyl alcohol mass fraction is 70%, after a period of time 3h is pre-chilled in a low temperature of 4 DEG C, The nano-fiber material of crosslinking is transferred in the ethanol-water solution that above-mentioned ethyl alcohol mass fraction is 70% and is eluted；Elution After 1h, it is again transferred in 4 DEG C of the ethanol-water solution that ethyl alcohol mass fraction is 95%；After eluting 1h, ethyl alcohol matter is transferred to It measures in 4 DEG C of the ethanol-water solution that score is 70%, elutes 1h.It is eluted using E-test, it is unreacted to remove Glutaraldehyde is repeated 3 times.
(4) nano-fiber material after elution is put into clean container and 3h is pre-chilled at -80 DEG C, then shift container It is lyophilized into freeze drier, the temperature that freeze-drying is arranged is that 3h is dried at -10 DEG C, is then dried for 24 hours, very at 20 DEG C again Reciprocal of duty cycle is set as 20pa.
(5) it by the nano-fiber material after freeze-drying, is put into high-speed shearing machine, setting revolving speed is 10000rpm/ Min, processing time are 25min, are tentatively sheared, obtain the pre- cutting object of strip；Then it sets revolving speed to 50000rpm/min after handling 10min to the pre- cutting object high speed shear of strip, carries out sieving using the mesh screen of 18 mesh, receives The formed body that passes through of collection sieving is to get to part nano-fibre cluster.
(6) the larger cluster not by mesh screen is placed again into high-speed shearing machine, setting revolving speed is 40000rpm/min； The processing time is 15min, obtains part nano-fibre cluster.
(7) the nano-fibre cluster sealed package that will be obtained after shearing carries out at the Co-60 gamma-ray irradiation sterilizing of 25kGY After reason, hemostasia products are obtained.
Embodiment 4
(1) carboxymethyl chitosan (CMCH) is dissolved in the mixed solution of purified water and hexafluoroisopropanol, wherein carboxymethyl The mass concentration of chitosan is 5% (g/mL), and stirring and dissolving obtains uniform polymer solution, as spinning solution.It will polymerization Object solution is placed in electrostatic spinning syringe, and the rate for adjusting micro-injection pump is 2mL/h, and the voltage for adjusting high pressure generator is 30kV, the reception distance for adjusting reception device is 15cm, and spinning environment relative humidity is set as 30%, and environment temperature is 40 DEG C, into Row electrostatic spinning.By high-voltage electrostatic spinning technology, the nanometer being interwoven by fiber filament and with porous structure is prepared Fibrous material.
(2) in 500mL reactor, 150mL ethanol solution is added, adds 50mL aqueous solution and 4mL glutaraldehyde Stirred and evenly mixed after solution, 2g nano-fiber material be put into reactor, carried out at 40 DEG C it is cross-linking modified, processing for 24 hours, handed over The nano-fiber material of connection.
(3) ethanol-water solution that configuration ethyl alcohol mass fraction is 70%, after a period of time 3h is pre-chilled in a low temperature of 4 DEG C, The nano-fiber material of crosslinking is transferred in the ethanol-water solution that above-mentioned ethyl alcohol mass fraction is 70% and is eluted；Elution After 1h, it is again transferred in 4 DEG C of the ethanol-water solution that ethyl alcohol mass fraction is 95%；After eluting 1h, ethyl alcohol matter is transferred to It measures in 4 DEG C of the ethanol-water solution that score is 70%, elutes 1h.It is eluted using E-test, it is unreacted to remove Glutaraldehyde is repeated 3 times.
(4) nano-fiber material after elution is put into clean container and 3h is pre-chilled at -80 DEG C, then shift container It is lyophilized into freeze drier, the temperature that freeze-drying is arranged is that 3h is dried at -10 DEG C, is then dried for 24 hours, very at 20 DEG C again Reciprocal of duty cycle is set as 20pa.
(5) it by the nano-fiber material after freeze-drying, is put into high-speed shearing machine, setting revolving speed is 10000rpm/ Min, processing time are 20min, are tentatively sheared, obtain the pre- cutting object of strip；Then it sets revolving speed to 30000rpm/min after handling 20min to the pre- cutting object high speed shear of strip, carries out sieving using the mesh screen of 18 mesh, receives The formed body that passes through of collection sieving is to get to part nano-fibre cluster.
(6) the larger cluster not by mesh screen is placed again into high-speed shearing machine, setting revolving speed is 40000rpm/min； The processing time is 10min, obtains part nano-fibre cluster.
(7) the nano-fibre cluster sealed package that will be obtained after shearing carries out at the Co-60 gamma-ray irradiation sterilizing of 25kGY After reason, hemostasia products are obtained.
Embodiment 5
(1) hydroxypropyl methyl cellulose (HPMC) material is dissolved in the mixed solution of hexafluoroisopropanol and water, wherein hydroxyl Propyl methocel mass concentration is 10% (g/mL), and stirring and dissolving obtains uniform polymer solution, as spinning solution. Simultaneously according to the fibrinogen (coagulation factor) of 20 mass % of hydroxypropyl methyl cellulose be added in above-mentioned polymer solution into Row dissolution.Polymer solution dissolved with fibrinogen is placed in electrostatic spinning syringe, the speed of micro-injection pump is adjusted Rate is 5mL/h, and the voltage for adjusting high pressure generator is 38kV, and the reception distance for adjusting reception device is 10cm, spinning environment phase 30% is set as to humidity, environment temperature is 40 DEG C, carries out electrostatic spinning.By high-voltage electrostatic spinning technology, prepare compound solidifying The nano-fiber material of blood factor being interwoven by fiber filament and there is porous structure.
(2) in 500mL reactor, 160mL ethanol solution is added, adds 40mL aqueous solution and 8mL glutaraldehyde After solution, and pH value is adjusted to acid (pH < 4), stirs and evenly mixs, 6g nano-fiber material is put into reactor, at 35 DEG C Carry out cross-linking modified, processing 48h, the nano-fiber material being crosslinked.
(3) ethanol-water solution that configuration ethyl alcohol mass fraction is 70%, after a period of time 3h is pre-chilled in a low temperature of 4 DEG C, The nano-fiber material of crosslinking is transferred in the ethanol-water solution that above-mentioned ethyl alcohol mass fraction is 70% and is eluted；Elution After 1h, it is again transferred in 4 DEG C of the ethanol-water solution that ethyl alcohol mass fraction is 95%；After eluting 1h, ethyl alcohol matter is transferred to It measures in 4 DEG C of the ethanol-water solution that score is 70%, elutes 1h.It is eluted using E-test, it is unreacted to remove Glutaraldehyde is repeated 3 times.
(4) nano-fiber material after elution is put into clean container and 3h is pre-chilled at -80 DEG C, then shift container It is lyophilized into freeze drier, the temperature that freeze-drying is arranged is that 3h is dried at 30 DEG C, is then dried for 24 hours, very at 20 DEG C again Reciprocal of duty cycle is set as 40pa.
(5) it by the nano-fiber material after freeze-drying, is put into high-speed shearing machine, setting revolving speed is 20000rpm/ Min, processing time are 10min, are tentatively sheared, obtain the pre- cutting object of strip；Then it sets revolving speed to 40000rpm/min after handling 30min to the pre- cutting object high speed shear of strip, carries out sieving using the mesh screen of 18 mesh, receives The formed body that passes through of collection sieving is to get to part nano-fibre cluster.
(6) the larger cluster not by mesh screen is placed again into high-speed shearing machine, setting revolving speed is 40000rpm/min； The processing time is 15min, obtains part nano-fibre cluster.
(7) the nano-fibre cluster sealed package that will be obtained after shearing carries out at the Co-60 gamma-ray irradiation sterilizing of 25kGY After reason, hemostasia products are obtained.
Performance test
Median D50Test
Test method: it takes product configuration to be measured at the weak solution of certain mass concentration, uses processor for ultrasonic wave (100W) By solution decentralized processing 10min, disperse nano-fibre cluster particle, uniformly, solution system reaches certain stable state.Using 2000 laser particle size analyzer of Mastersizer of Malvern company, Britain is tested.Before measurement, laser particle size analyzer 30min need to be preheated in advance.When measurement, firstly, instrument is carried out to light, control measurement background state is normal.It then, will be scattered Sample disposably pours into sample measuring cell, and rinses residual sample with deionized water and pour into sample cell, clicks " analysis " rapidly, It carries out sample measurement and saves data.It is tested with the hemostasia products of embodiment 1-5, test result is as shown in table 1.
1 median D of table50Test result
Sample ID Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5
Median (μm) 260 480 350 300 200
As can be seen from Table 1, in the hemostatic material of the application nano-fibre cluster with median D50The ruler of expression It is very little between 200 μm -500 μm.
Specific surface area test
Test method: product to be measured is taken to be put into the sample cell of analysis instrument, wherein analysis instrument is quickly full-automatic compares Surface area and Porosimetry, model U.S. health tower NOVA 4200e.Under the conditions of low temperature (liquid nitrogen bath), lead into sample cell Enter a certain amount of Adsorbate Gas (N2), determine sample to adsorption molecule according to the variation of absorption front and back gas volume (N2) adsorbance；The ratio table of solid matter is measured with reference to standard GB/T/T24533-2009-gas absorption BET principle Area.
The calculation of specific surface area are as follows: be put into the sample in gaseous environment, material surface (extra-granular and inside The surface area in gap) physical absorption will occur at low temperature.When absorption reaches balance, the adsorbed gas of equilibrium adsorptive pressure is measured The scale of construction calculates sample mono layer adsorption amount according to BET equation, to calculate the specific surface area of sample.Wherein, BET Equation are as follows:
Figure BDA0001452532850000201
In formula:
P --- adsorbate partial pressure, unit Pa；
P0--- adsorbent saturated vapor pressure, unit Pa；
V --- the practical adsorbance of sample, unit cm3；
Vm--- single layer saturated extent of adsorption, unit cm3；
C --- constant relevant to sample adsorption capacity.
It is tested with the hemostasia products of embodiment 1-5, test result is as shown in table 2.
2 specific surface area test result of table
Sample ID Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5
Specific surface area (m2/g) 22.187 18.321 15.477 12.385 11.308
As can be seen from Table 2, hemostasia products of the invention have very high specific surface area.
Porosity test
Porosity measures as follows: the porosity of porous material is determined with solvent completion method.Since ethyl alcohol holds It easily infiltrates through without causing Material shrinkage and swelling inside porous material, therefore using ethyl alcohol as reagent.
Test method are as follows: be packed into ethanol solution in the small beaker of 50mL, weigh the hemostasia products for being dried to weight (quality m1) be soaked in ethyl alcohol, circulation is evacuated to hemostasia products there is no bubble spilling, weighs containing ethyl alcohol and hemostasis The beaker total weight of product is m2, then the hemostasia products taking-up by inside containing ethyl alcohol, remaining beaker and ethyl alcohol are weighed as m3, each sample is 3 times parallel, as a result as shown in table 3 below.
Measure porosity P are as follows:
P=(m2-m3-m1)/(m2-m3) × 100%
Wherein: (m2-m3-m1) be hemostasia products hole contained in ethyl alcohol quality；
(m2-m3) it is the hemostasia products gross mass containing ethyl alcohol.
It is tested with the hemostasia products of embodiment 1-5, test result is as shown in table 3.
3 porosity test result of table
Sample ID Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5
Porosity % 90 82 78 64 71
As can be seen from Table 3, the application hemostasia products have very high porosity.
Saturated water absorption test
Test method: by the sample (m of certain mass1) be placed in culture dish, be added be preheated to (37 ± 1) DEG C 0.9% Physiological saline, the quality of physiological saline are 40 times of material to be tested.Culture dish is moved into drying box, is protected at (37 ± 1) DEG C Hold 30min.Sample is taken out with tweezers, dangle 30s, with electronic balance precise m2, it is measured in parallel 3 times.It is obtained by calculation Saturated water absorption (X), the calculation formula of saturated water absorption (X) are as follows: X=(m2-m1)/m1× 100%.
It is tested with the hemostasia products of embodiment 1-5, test result is as shown in table 4, wherein n is to be measured in parallel number.
4 saturated water absorption test result (n=3) of table
Sample ID Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5
Saturated water absorption % 2812±15 2550±10 2370±8 1951±12 1733±10
As can be seen from Table 4, the application hemostasia products have very high saturated water absorption.
Heap density measurement
Test method: it is V (cm that material, which is freely fallen into volume,3), quality m1(g) in graduated cylinder, stack material freely Reach volume, then weighs the overall quality m of graduated cylinder and material2(g), then heap density (g/cm3)=(m2-m1)/V。
It is tested with the hemostasia products of embodiment 1-5, the results are shown in Table 5, wherein n is parallel testing number.
5 heap density measurement result (n=3) of table
Sample ID Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5
Heap density (g/cm3) 0.027±0.001 0.016±0.002 0.022±0.002 0.041±0.003 0.033±0.002
Hemostasis validity test
Test method: using rabbit liver oozing of blood model, cut off the abdomen rabbit hair, and abdomen is opened in the center of standard, dissociates, exposure liver It is dirty；The wound of 10 × 10 × 2mm is formed in liver same area；The surface of a wound is cleared up with gauze, is covered with the hemostasia products of identical weight Lid wound surface, and gelfoam is covered above, 30s is pressed, sponge is removed and observes wound oozing of blood situation.When record hemostasis Between, evaluation hemostasis validity.
It is tested with product made from the embodiment of the present invention 1 (experimental group), while using reference product (commercial product 1) As positive control, experimental group and control group parallel group number are n=10.
As a result as shown in Fig. 2, the bleeding stopping period of reference product (commercial product) is 308.8s；The embodiment of the present invention 1 is made Hemostasia products bleeding stopping period be 135.5s；, there is significant difference in P value=0.03, P value < 0.05.Therefore, production of the invention Bleeding stopping period of the bleeding stopping period of product significantly less than commercial product.
Degradability test
Test method: using the product of the embodiment of the present invention 1 as test material (experimental group), using commercial product as control Material (control group).
It is tested using rabbit muscular grafting.The abdomen rabbit hair is cut off, abdomen is opened in the center of standard, cuts skin and muscle, implantation Material, material weight 0.01g are sutured after fixing, then skin closure is closed, postoperative antibiotic care three days.To setting in advance After the fixed observation period (postoperative 1W (1 week), postoperative 2W (2 weeks), postoperative 4W (4 weeks)), dissection is photographed to record, and tissue is taken to send disease Reason analysis, pathological analysis evaluate biological tissue's compatibility of implantation site material.
Pathological examination is shown, as shown in figure 3, hemostasia products of the invention have been degraded completely at 4W (4 weeks).And commercially available production Product can also see the not degradable absorption of some materials at 4W (4 weeks).Also, the tissue verifying stimulation of experimental group is also below right According to group.Therefore, hemostatic material of the invention has good tissue biocompatibility.In addition, during experiment, Neng Gouguan The hemostatic material for observing the application has more excellent adhesion property.
The above embodiment of the present invention be only to clearly illustrate example of the present invention, and not be to the present invention Embodiment restriction.For those of ordinary skill in the art, it can also make on the basis of the above description Other various forms of variations or variation.There is no necessity and possibility to exhaust all the enbodiments.It is all of the invention Made any modifications, equivalent replacements, and improvements etc., should be included in the protection of the claims in the present invention within spirit and principle Within the scope of.

Claims (26)

1. a kind of hemostatic material, which is characterized in that the hemostatic material includes nano-fibre cluster, and the nano-fibre cluster is derived from The nano-fiber material of crosslinking,
The nano-fibre cluster using its geometric center as starting point towards three-dimensional space any direction size in 5 μm~500 μm models In enclosing；And/or in the hemostatic material nano-fibre cluster with median D50The size of expression is between 100 μm -500 μm；
The nano-fibre cluster has a porous structure, and the nano-fibre cluster has and by more nano short fibers mutually overlaps shape At cross structure；The diameter of the nano short fiber is between 1nm~1000nm, and length is at 1000 μm or less；
The porosity of the hemostatic material is 50%~90%.
2. hemostatic material according to claim 1, which is characterized in that nano-fibre cluster with middle position in the hemostatic material Partial size D50The size of expression is between 200 μm -400 μm.
3. hemostatic material according to claim 1, which is characterized in that the porosity of the hemostatic material be 70%~ 90%.
4. hemostatic material according to claim 1, which is characterized in that the specific surface area of the hemostatic material is 4m2/ g~ 50m2/g。
5. hemostatic material according to claim 4, which is characterized in that the specific surface area of the hemostatic material is 10m2/ g~ 40m2/g。
6. hemostatic material according to claim 1-5, which is characterized in that the heap density of the hemostatic material is less than 0.06g/cm3。
7. hemostatic material according to claim 6, which is characterized in that the heap density of the hemostatic material is 0.025g/cm3 ~0.05g/cm3。
8. hemostatic material according to claim 1-5, which is characterized in that the water absorption rate of the hemostatic material is greater than 1500%.
9. hemostatic material according to claim 8, which is characterized in that the water absorption rate of the hemostatic material 2000%~ Between 3000%.
10. hemostatic material according to claim 1-5, which is characterized in that the nano-fiber material is originated from tool Have biocompatibility and can organism degradation absorb polymer material, the nano-fiber material by fiber filament interweave and At.
11. hemostatic material according to claim 10, which is characterized in that the nano-fiber material is coma, fiber Beam or tunica fibrosa.
12. hemostatic material according to claim 1-5, which is characterized in that the crosslinking is in crosslinking agent have Under crosslinking.
13. hemostatic material according to claim 12, which is characterized in that the crosslinking agent and the nano-fiber material Mass ratio is 0.01~2:1.
14. hemostatic material according to claim 13, which is characterized in that the crosslinking agent and the nano-fiber material Mass ratio is 0.1~1:1.
15. hemostatic material according to claim 1-5, which is characterized in that the hemostatic material also includes medicine Object.
16. hemostatic material according to claim 15, which is characterized in that the drug includes fibrin ferment, coagulation factor, life The combination of one or more of the long factor.
17. a kind of preparation method of -16 described in any item hemostatic materials according to claim 1, which is characterized in that including following Step:
Electrostatic spinning step: the nano-fiber material is prepared by electrostatic spinning；
Cross-linking step: crosslinking Treatment, the Nanowire being crosslinked are carried out to the nano-fiber material in the presence of a crosslinking agent Tie up material；
It shears step: shear treatment being carried out to the nano-fiber material of the crosslinking, obtains formed body；
Sifting step: sieving processing is carried out to the formed body.
18. the preparation method of hemostatic material according to claim 17, which is characterized in that the crosslinking agent includes: carbonization The combination of one or more of diimine, n-hydroxysuccinimide, Geniposide or aldehyde compound.
19. the preparation method of hemostatic material according to claim 18, which is characterized in that the crosslinking agent includes carbonization two Imines and n-hydroxysuccinimide.
20. the preparation method of hemostatic material according to claim 19, which is characterized in that the carbodiimides and N- hydroxyl The mass ratio of base succinimide is 1~4:1.
21. the preparation method of the described in any item hemostatic materials of 7-20 according to claim 1, which is characterized in that at the shearing Reason includes,
Pre- shearing step carries out the nano-fiber material of the crosslinking preliminary under the revolving speed of 10000~20000rpm/min Shear treatment obtains pre- cutting object, and/or
High speed shear step carries out at high speed shear the pre- cutting object under the revolving speed of 30000~50000rpm/min Reason.
22. the preparation method of the described in any item hemostatic materials of 7-20 according to claim 1, which is characterized in that at the sieving Reason collects the formed body that sieving passes through to carry out sieving using the mesh screen of 18 mesh.
23. the preparation method of hemostatic material according to claim 22, which is characterized in that the preparation method further includes,
Step is sheared again: under the revolving speed of 40000~50000rpm/min, the unsanctioned formed body of sieving being cut again Cut processing.
24. the preparation method of the described in any item hemostatic materials of 7-20 according to claim 1, which is characterized in that at the shearing Reason is carried out in the state of being passed through flowing gas.
25. the preparation method of the described in any item hemostatic materials of 7-20 according to claim 1, which is characterized in that the crosslinking step Suddenly between shearing step further include: elution step and/or freeze-drying step.
26. a kind of hemostatic article characterized by comprising -16 described in any item hemostatic materials according to claim 1, or The hemostatic material that the preparation method of the described in any item hemostatic materials of claim 17-25 is prepared.
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WO2019011333A1 (en) * 2017-07-14 2019-01-17 广州迈普再生医学科技股份有限公司 Haemostatic material, haemostatic fibre membrane, and haemostatic product
CN108295319B (en) * 2018-03-08 2021-05-11 山东省药学科学院 Medical nanofiber-reinforced hydrophilic composite material and preparation method and application thereof
JP7320078B2 (en) * 2019-04-30 2023-08-02 チュンイェン ヂョン Biocellulose fiber, hemostatic dressing containing same and related applications
CN113117131B (en) * 2019-12-31 2023-01-03 广州迈普再生医学科技股份有限公司 Nanofiber microsphere material and preparation method and application thereof
CN113117132B (en) * 2019-12-31 2022-11-22 广州迈普再生医学科技股份有限公司 Absorbable expansion type nano short fiber powdery material and preparation method and application thereof
CN113117133B (en) * 2019-12-31 2023-03-14 广州迈普再生医学科技股份有限公司 Fiber aggregate and preparation method and application thereof
CN112807477B (en) * 2020-12-30 2023-03-07 广州迈普再生医学科技股份有限公司 Composite hemostatic material and preparation method thereof
CN114681678B (en) * 2020-12-31 2023-04-18 广州迈普再生医学科技股份有限公司 Nanofiber sponge and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753746A (en) * 2010-09-14 2012-10-24 纺织和塑料研究协会图林根研究院 Highly functional spunbonded fabric made from particle-containing fibres and method for producing same
CN106012297A (en) * 2016-06-30 2016-10-12 吉林大学 Method for preparing medical complex fiber three-dimensional structure dressing

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5871234B2 (en) * 2012-03-23 2016-03-01 国立研究開発法人物質・材料研究機構 Method for producing synthetic collagen nanofiber

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753746A (en) * 2010-09-14 2012-10-24 纺织和塑料研究协会图林根研究院 Highly functional spunbonded fabric made from particle-containing fibres and method for producing same
CN106012297A (en) * 2016-06-30 2016-10-12 吉林大学 Method for preparing medical complex fiber three-dimensional structure dressing

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