CN107041964A - Composite, preparation method and use - Google Patents
Composite, preparation method and use Download PDFInfo
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- CN107041964A CN107041964A CN201610082226.XA CN201610082226A CN107041964A CN 107041964 A CN107041964 A CN 107041964A CN 201610082226 A CN201610082226 A CN 201610082226A CN 107041964 A CN107041964 A CN 107041964A
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- microballoon
- hydroxyapatite
- biodegradable polyester
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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
- A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
- A61L24/0084—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
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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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L31/127—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing fillers of phosphorus-containing inorganic materials
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Surgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Composite Materials (AREA)
- Inorganic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The present invention relates to a kind of composite and its preparation method and application.The composite, particularly compound hemostatic microballoon have the microsphere surface of open-celled structure and the hydroxyapatite for coming and being enriched with the surface of the microsphere are exposed from tapping.It is of the invention that compound is first prepared with Biodegradable polyester and hydroxyapatite, primary microballoon is then prepared by solvent evaporation method, then primary microballoon degrade having obtained compound hemostatic microballoon.In hemostasis is participated in, Biodegradable polyester and hydroxyapatite have cooperative effect, Biodegradable polyester provides favourable carrier for hydroxyapatite, obtained hemostatic microsphere has larger specific surface area, also the place provided convenience for blood coagulation so that compound hemostatic microballoon preferably can fit with bleeding part.
Description
Technical field
The invention belongs to medical product field, and in particular to a kind of composite, preparation method and use.
Background technology
The bleeding and bone tissue damage for being difficult to control are war, traffic accident and the murderous master of other contingencies
Reason is wanted, is also the problem that emergency care of trauma and surgical operation are frequently encountered, therefore exploitation has extraordinary high property
The biomaterial and product of energy are for wartime first aid and usually seek medical advice all with important social effect.
Counted according to the Ministry of Public Health in 2007, annual all kinds of injuries occur about 200,000,000 person-times, because of war, traffic thing
Therefore, the people of injury scope number about 700,000~750,000 such as major natural disasters, excessive blood loss is to cause died of wounds
The biggest factor.The death that the multiple dead and wounded data statistics of war also discloses 30%~60% comes from excessive blood loss.Mesh
Before untill, the country be used in, the emergency survival hemostasia products of severe bleeding it is few, the conventional hemostasis equipped with oneself
Agent has tourniquet, chitosan, gauze and Yunnan Baiyao, and they are in, the effect of the quick-acting haemostatic powder of severe bleeding
It is limited.What hospital commonly used has fibrin ferment, Fibrin Glue etc., but these hemostasia products are expensive, thus
Urgently develop good, the cheap styptic of haemostatic effect.
With the development of science and technology, the research and development of hemostatic material are maked rapid progress.In the market using more
Extensive hemostatic material mainly has biological products class, chitosan class and Aluminosilicates three major types hemostatic material.
In addition, there is also some other commercialization hemostasia products, as using farina as primary raw material
TraumaDex etc..In actual use, the validity of pressing time and wound form to hemostatic material
There is considerable influence, thus also need to select hemostatic material in use.
1. biological products class
Mainly include fibrin ferment, factor XIII and fibrinogen for the biological products that external hemorrhage is stopped blooding
Deng clotting factor.It is most widely used at present and effectively Fibrin Glue, the production of in the market Fibrin Glue
Kind class is various, and most of product is all by fibrinogen, fibrin ferment, factor XIII and AKOLINE
Four component compositions.
Fibrin Glue needs the material mixing in two elements, and fibrin ferment, suppression peptide ferment when in use
It is stored refrigerated Deng needs, thus it is typically employed in the occasions such as surgical hemostasis, in other lifesaving applications phases
To less.
2. Aluminosilicates
The research of alumino-silicate hemostatic material focuses primarily upon 5A zeolites and kaolin, and they have preferable body
Outer coagulating effectiveness and biocompatibility, and all there are commercialization hemostasia products.
First generation Quikclot product main components are 5A zeolites, have during applied to external hemorrhage and significantly put
Fuel factor, thus early stage silicic acid alumino-silicate hemostatic material exploitation concentrate on reduction Quikclot heat release effect
Should be with hemostatic material two aspect of the exploitation without exothermic effect.Preferable development is all achieved in these two aspects, such as
Quikclot fuel factor can be reduced by ion exchange or pre- water suction, and have developed corresponding product
QuikClot Sport Silverr.And also obtained by the exploitation of the low exothermic effect material such as kaolin, montmorillonite
Corresponding commercialization hemostasia products Combat Gauze and Woundstat.Although in zoopery hemostasis
In terms of effect and survival rate, the commercially produced product Woundstat by main component of montmorillonite is not showed
Go out shortcoming, but it can cause endothelial injuries when applied to external hemorrhage wound, even into vascular circulation,
Organ tip is set to produce thrombus.
3. chitosan class
Current bleeding-stopping dressing is chitin and chitosan in one of application of medical field most future.Chitosan
The research of hemostatic function, is most reported earlier than last century the eighties.Chitosan can provide non-for tissue growth
Albumen stromal matrix, while cytotoxicity and the cell differentiation effect of activating macrophage.Degradation of chitosan is N-
After acetyl group-β-D- Glucosamines, it can further promote synthesis and the collagen egg of wound hyaluronic acid
White deposition, promotes wound healing, suppresses scar and is formed.
Commercialization chitosan class hemostasia products Celox is shown better than other in numerous animal bleeds models
The effect of chitosan hemostasia products, but the influence factor of chitosan haemostatic effect is still failed to understand.
Therefore, at present in the urgent need to there is the material that a kind of coagulating effectiveness is improved, to solve existing hemostasis
The drawbacks of material is present.
The content of the invention
The present invention is intended to provide a kind of composite, preparation method and use, the blood coagulation of the composite
Effect and biocompatibility are significantly improved.
To achieve these goals, the invention provides a kind of composite, the composite includes biology
Degradability polyester and hydroxyapatite.
According to the present invention, the composite is Biodegradable polyester and hydroxyapatite through compound, solvent
Compound hemostatic microballoon made from volatility process.
Preferably, the compound hemostatic microballoon has the microsphere surface carrier of open-celled structure and naked by perforate
Expose and be enriched in the hydroxyapatite of the microsphere surface.
According to the present invention, the number-average molecular weight of the microballoon is 10000~500000, and particle diameter is 5~500 μm；
It is further preferred that the molecular weight of the compound hemostatic microballoon is 20000~50000, such as 30000~40000；
Grain diameter is 50~350 μm, such as 150~250 μm, is specifically as follows 200 μm.
According to the present invention, the Biodegradable polyester refers to the polyester polymers with biodegradation character.
The preference of above-mentioned Biodegradable polyester can enumerate poly adipate succinic acid ester-poly terephthalic acid fourth
It is ethylene terephthalate copolymers, PHA, polyglycolic acid, poly butylene succinate, poly-epsilon-caprolactone, poly-
Succinic acid-butanediol ester-poly adipate succinic acid ester copolymer, poly butylene succinate-poly terephthalic acid fourth
Ethylene terephthalate copolymers, polydiethylene glycol sebacate-polybutylene terephthalate (PBT) copolymer, polylactide are (poly-
Lactic acid), PGA (polyglycolic acid), one kind in polycaprolactone and polylactide-co-glycolide
Or it is a variety of；Preferably polylactide.
The Biodegradable polyester monomer is that the raw material of the polyester can be obtained by polymerisation, for example may be used
Think the one or more in glycolide, lactide and caprolactone.
Preferably, the particle diameter of the hydroxyapatite is 10nm~10 μm；More preferably
10nm~200nm；More preferably 20~100nm.
Preferably, the compound hemostatic microballoon is the microballoon after degraded.
The present invention also provides the preparation method of a kind of composite, particularly compound hemostatic microballoon, including following
Step：
1) complex solution is prepared：Organic Biodegradable polyester and inorganic hydroxyapatite are answered
Close, obtained compound is dissolved in organic solvent, complex solution is obtained；
2) complex solution is prepared into by primary microballoon using solvent evaporation method；
3) the primary microballoon is degraded, obtains the organo-mineral complexing hemostasis based on hydroxyapatite micro-
Ball.
Preferably, the complex method of Biodegradable polyester and inorganic hydroxyapatite can be multiple for physics
Close and chemically composited.The physics is compound to be referred to mix Biodegradable polyester and inorganic hydroxyapatite.
The described chemically composited open loop for referring to trigger hydroxyapatite and Biodegradable polyester by hydroxyl is poly- anti-
It should be combined.The present invention is more preferably chemically composited, is more preferably carried out using the method for chemical graft
It is compound.
In one particular embodiment of the present invention, it for example can be by hydroxyapatite and biology that physics is compound
Degradability polyester dispersion is stirred vigorously in organic solvent such as chloroform, then using solvent such as hexamethylene
Sedimentation, compound is obtained after vacuum drying.Drying temperature can be 30~60 DEG C, and such as 45 DEG C, the time can
Think 12~120 hours, such as 72 hours.The weight ratio of hydroxyapatite and Biodegradable polyester can be with
For (5:100)~(50:100), such as 10:100、20:100、30:100.
In another specific embodiment of the present invention, chemical method for example can be the reaction in anhydrous and oxygen-free
Under the conditions of, hydroxyapatite, lactide, stannous octoate (SnOct2) and toluene add reaction tube in, afterwards
Capping pipe is reacted, for example, 12~120 hours can be reacted under 60~180 DEG C (such as 120 DEG C) (such as
48 hours).Reaction is finished, separation product, for example, dissolved using solvent such as dichloromethane, hexamethylene sedimentation
Obtain product.Product is used after 45 DEG C of vacuum drying chamber is dried 72 hours.
Wherein the mol ratio of stannous octoate and lactide can be (1:10)~(1:100), such as (1:40)~(1:60),
It is specifically as follows 1:50；The weight ratio of hydroxyapatite and lactide can be (5:100)~(50:100), for example
10:100、20:100、30:100。
Wherein, compound hemostatic microballoon of the invention can be prepared by solvent evaporation method.It is prepared by solvent evaporation method
The step of porous microsphere, includes：First prepare finite concentration (C1) polymer/organic solvent solution (oil phase Oil),
The solution is placed in ultrasonic disintegrator probe lower section, and water-bath on the rocks, ultrasonic emulsification is carried out by the parameter of setting,
At this moment syringe needle is stretched between probe and chamber wall, the interior aqueous phase that the oil phase injection into ultrasound is prepared
(W1), system is converted into the emulsion E of white by water white transparency1.Then the emulsion E prepared is drawn with syringe1,
Churned mechanically outer aqueous phase (W is instilled dropwise2) in, continue to stir after certain time, wash, collect.
According to the present invention, the step of complex solution is prepared into primary microballoon using solvent evaporation method includes：
21) complex solution is mixed with interior aqueous phase, emulsified for the first time, obtain first emulsified solution；
Preferably, the step 21) in complex solution is emulsified for the first time using high speed shear method, obtain
To first emulsified solution；
22) the first emulsified solution is mixed with outer aqueous phase, be stirred at room temperature, second emulsifying obtains oil-in-water
Solution, i.e., primary microballoon.
Preferably, the step 22) in also include：Microballoon is taken out after being stirred at room temperature, with deionized water repeatedly
Centrifuge washing removes unnecessary NaOH, is obtained after drying with good through-hole structure based on hydroxyapatite
Organo-mineral complexing hemostatic microsphere.
According to the present invention, Biodegradable polyester is polylactide, PGA, polycaprolactone and polylactide
One or more in glycolide copolymer；Preferably polylactide.Preferably, the grain of the hydroxyapatite
Footpath is 10nm~10 μm；More preferably 10nm~200nm；More preferably 20~100nm.
According to the present invention, step 1) in, Biodegradable polyester and hydroxyapatite are according to weight (100：
1)~(1:1) ratio is dissolved in the organic solvent of 5~40 times of weight, obtains complex solution；
Preferably, the ratio of the organic Biodegradable polyester and inorganic hydroxyapatite for example can be with
For 2:1.
Preferably, the organic solvent can be dichloromethane.
According to the present invention, the interior aqueous phase and the outer aqueous phase are according to (0~1) by surfactant and water:50
G/mL (i.e. the volume ratio of the weight of surfactant and water) is well mixed what is obtained；The surfactant
Selected from span60, span80, the one or more in tween80 and PVA (polyvinyl alcohol)；Preferably,
The weight of the surfactant is more than 0.
The volume ratio of the complex solution and interior aqueous phase is (1:1)~(20:1)；For example can be 4:1.
The volume ratio of the first emulsified solution and outer aqueous phase is (1:10)~(1:50).
According to the present invention, step 3) in, the time is stirred at room temperature for 1~6 hour, for example, can be 3 hours.
In accordance with the present invention it is preferred that, the degraded is carried out using the method for hydrolysis, aminolysis or enzyme degraded.
According to the present invention, the hydrolysis is carried out in alkaline solution；The alkaline solution can for KOH or
The NaOH aqueous solution；It is further preferred that the concentration of the KOH aqueous solution is 0.01~10M, it is described
The concentration of the NaOH aqueous solution is 0.01~2M, for example, can be 0.5M.
Preferably, the aminolysis is carried out in the aqueous solution of amine；The amine is methylamine, ethylenediamine or triethylamine；
It is further preferred that the concentration of the aqueous solution of the methylamine, ethylenediamine or triethylamine is 0.2~10M.
Used in enzyme degraded in the form of the cushioning liquid or the aqueous solution of enzyme, it is preferable that the enzyme is
There is the enzyme of selectivity to Biodegradable polyester；It is further preferred that the cushioning liquid is slow for phosphate
Rush solution and/or tris cushioning liquid.
According to the present invention, in addition to the step of sterilized to the compound hemostatic microballoon；It is preferred that with Co 60 spoke
According to sterilizing.Present invention also offers a kind of composite, particularly compound hemostatic microballoon is in blood coagulation and/or hemostasis
In application.
Beneficial effects of the present invention：
The present invention is first by preparing the compound of Biodegradable polyester and hydroxyapatite, then by molten
Agent volatility process prepares primary microballoon, then primary microballoon is degraded to improve its haemostatic effect, so that
The organo-mineral complexing hemostatic microsphere based on hydroxyapatite is arrived.The organo-mineral complexing hemostatic microsphere has
Good open-celled structure, and hydroxyapatite exposed come by perforate and is equably enriched in perforate microballoon
Surface, therefore haemostatic effect is excellent.
During compound hemostatic microballoon participates in hemostasis, have between Biodegradable polyester and hydroxyapatite
There is preferable cooperative effect, Biodegradable polyester provides favourable carrier function for hydroxyapatite, and
Compound hemostatic microballoon has larger specific surface area, the place also provided convenience for blood coagulation again so that compound
Hemostatic microsphere preferably can fit with bleeding part.Compound hemostatic microballoon provided by the present invention being capable of mechanism
Property participation coagulation process, wherein the hydroxyapatite being enriched with pass through powerful protein adsorption and release calcium ion
Carry out mechanistic participation, it is to avoid the excessive blood loss caused by water imbibition styptic, and haemostatic effect is excellent.
The compound hemostatic microballoon of the present invention, can be absorbed, good biocompatibility by human body, available for surgery hand
The hemostasis of art, can directly be sprayed on people, mammal etc. has the blood surface of a wound to be stopped blooding, and is alternatively arranged as outer
Section prevents adhesion, promotion organization healing material.In addition, the present invention utilizes industrialized simple raw material, source is wide
It is general, human body is had no toxic side effect, environmentally safe, environmental protection.And by easy controllable preparation work
Skill, has just obtained a kind of good biocompatibility, the excellent organic-inorganic based on hydroxyapatite of coagulating effectiveness
Compound hemostatic microballoon, has a extensive future.
Brief description of the drawings
Before Fig. 1 is the hydrolysis of the organo-mineral complexing hemostatic microsphere based on hydroxyapatite of the embodiment of the present invention 1
Scanning electron microscope (SEM) photograph afterwards, a1, a2 is the primary microballoon before hydrolysis, and b1, b2 is based on hydroxy-apatite after hydrolyzing
The organo-mineral complexing hemostatic microsphere of stone；
Before Fig. 2 is the hydrolysis of the organo-mineral complexing hemostatic microsphere based on hydroxyapatite of the embodiment of the present invention 2
Scanning electron microscope (SEM) photograph afterwards, a1, a2 is the primary microballoon before hydrolysis, and b1, b2 is based on hydroxy-apatite after hydrolyzing
The organo-mineral complexing hemostatic microsphere of stone.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, below in conjunction with accompanying drawing and reality
Example is applied, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only used
To explain the present invention, it is not intended to limit the present invention.
Unless otherwise indicated, reagent used in the present invention is commercially available.Part used in the present invention
Reagent or sample are as follows：Anti-freezing rabbit blood now takes out existing use, hydroxyapatite (article No. 677418,10~200nm of particle diameter,
Specific surface area is more than or equal to 9.4m2g-1) buy in aldrich companies.Lactide monomer is purchased from Ke Bien-pula
Gram China (Corbion Purac).
Embodiment 1
1) the primary microballoon with closed pore structures is prepared
A) complex solution is prepared：
Using chemical method：Under the reaction condition of anhydrous and oxygen-free, by foregoing hydroxy apatite, lactide monomer
With stannous octoate SnOct2Reaction tube is added with toluene, capping pipe is reacted, reacted at 120 DEG C
48 hours.Reaction is finished, and product is dissolved using solvent such as dichloromethane, hexamethylene sedimentation, afterwards at 45 DEG C
Dried 72 hours in vacuum drying chamber.The product being dried to obtain is dissolved in dichloromethane, compound is obtained molten
Liquid.
Wherein the ratio of stannous octoate and lactide monomer is 1:50 (mol ratios), hydroxyapatite and third is handed over
The weight ratio of ester monomer is 20:100.
B) by interior aqueous phase NH of the 1.25ml concentration for 0.1g/mL4HCO3Solution is added to above-mentioned preparation
In the dichloromethane solution of 5ml compound, ultrasonic emulsification obtains colostric fluid.
C) it is rapid that gained colostric fluid is poured into the surface modification PVA water that 200ml concentration is 0.001g/mL
In solution, mechanical agitation 3 hours, finally give the primary microballoon with closed pore structures at room temperature.
The above-mentioned primary microballoon scanning electron microscope (SEM) photograph with closed pore structures is as shown in Fig. 1 a1 and a2.Can be with
Find out, it has cap holes, hole surface or space are covered by film.
2) primary microballoon is hydrolyzed, prepares with open-celled structure and surface enrichment has the compound of hydroxyapatite
Hemostatic microsphere.
By 0.1g steps 1) in the primary microballoon with closed pore structures for preparing be soaked in 20ml 0.5M
NaOH solution in, take out microballoon after being stirred at room temperature 10 minutes, be centrifuged repeatedly with 200ml deionized waters
Washing is removed and is freeze-dried 24 hours at unnecessary NaOH, -120 DEG C, is obtained with good open-celled structure
Compound hemostatic microsphere powder, is sterilized using co-60 radiation afterwards.
The molecular weight of the compound hemostatic microballoon of above-mentioned preparation is 30000, and grain diameter is 200 ± 15 μm.
The ESEM of the compound hemostatic microballoon with good open-celled structure prepared in embodiment 1 is such as Fig. 1
A1 in b1, b2, with Fig. 1, a2 (i.e. primary microballoon) contrast, it is seen that primary microballoon is covered in after hydrolysis
Film between surface and its hole disappears, and has obtained having good open-celled structure and surface enrichment has hydroxyapatite
Compound hemostatic microballoon.
Illustrate to eliminate the polyester film being covered on hydroxyapatite by hydrolysis so that nano level hydroxyl phosphorus
Lime stone can be exposed from perforate, due to the crystal structure and nanoscale of hydroxyapatite, so more
Be conducive to adhesion protein and release calcium ion, so as to drastically increase the hemostasis of compound hemostatic microballoon and/or coagulate
Blood effect.
Embodiment 2
1) the primary microballoon with closed pore structures is prepared
A) complex solution is prepared
Using chemical method：Under the reaction condition of anhydrous and oxygen-free, by foregoing hydroxy apatite, lactide and pungent
Sour stannous SnOct2Reaction tube is added with toluene, capping pipe is reacted, 48 are reacted at 120 DEG C small
When.Reaction is finished, and product is dissolved using solvent such as dichloromethane, hexamethylene sedimentation, afterwards in 45 DEG C of vacuum
Dried 72 hours in drying box.The product being dried to obtain is dissolved in dichloromethane, complex solution is obtained.
Wherein the ratio of stannous octoate and lactide is 1:50 (mol ratios)；Hydroxyapatite and lactide
Weight ratio is 10:100.
B) by 1.25ml 10wt% interior aqueous phase NH4HCO3Solution is added to the 5ml concentration of above-mentioned preparation
In dichloromethane solution for 3.13wt% compound, emulsification obtains colostric fluid.
C) gained colostric fluid is poured into 200ml, the 0.1wt% PVA aqueous solution rapidly, it is mechanical at room temperature
3h is stirred, the primary microballoon with closed pore structures is finally given.
The scanning electron microscope (SEM) photograph of the primary microballoon with closed pore structures is as shown in Fig. 2 a1 and a2.Can
To find out, it has cap holes, and hole surface or space are covered by film.
2) the compound hemostatic microballoon for having hydroxyapatite to be enriched with open-celled structure and surface is prepared
By 0.1g steps 1) in the primary microballoon with closed pore structures for preparing be soaked in 20ml 0.5M
NaOH solution in, take out microballoon after being stirred at room temperature 10 minutes, be centrifuged repeatedly with 200ml deionized waters
Washing removes unnecessary NaOH, and the compound hemostatic microballoon with good through-hole structure is obtained after drying, and uses
Co-60 radiation sterilizes.
The molecular weight of the compound hemostatic microballoon prepared in embodiment 2 is 40000, and grain diameter is 200 ± 15 μm.
ESEM such as Fig. 2 of compound hemostatic microballoon with good through-hole structure b1, b2, with Fig. 2 a1,
A2 is contrasted, it is seen that the film being covered in after hydrolysis between primary microsphere surface and its hole disappears, and obtains with good
Good open-celled structure and surface has the compound hemostatic microballoon that hydroxyapatite is enriched with.
External coagulating effectiveness experiment：
The present invention is commented by the external clotting time of the organo-mineral complexing hemostatic microsphere based on hydroxyapatite
Estimate its thromboplastic effect.
Blood coagulation method of testing is in vitro：The anti-freezing rabbit plasma that 2ml is fresh is taken, appropriate 0.2M CaCl are added2It is molten
Liquid, it is 7~8 minutes to make the rabbit plasma natural clotting time, and timing course sample is shaken up on mixed instrument spiraling.
Outside testing microsphere during haemostatic effect, compound hemostatic microballoon is first added, blood, CaCl is sequentially added2。
The compound hemostatic microballoon prepared in 1g embodiments 1 is taken, follow-up coagulation time test is carried out, during blood coagulation
Between be 87s.
The compound hemostatic microballoon prepared in 1g embodiments 2 is taken, follow-up coagulation time test is carried out, during blood coagulation
Between be 109s.
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, and
Not limiting the present invention, any modification for being made within the spirit and principles of the invention, equivalent substitution
With improve etc., should be included in the scope of the protection.
Claims (10)
1. a kind of composite, it is characterised in that including Biodegradable polyester and hydroxyapatite.
2. composite according to claim 1, it is characterised in that its be Biodegradable polyester and
Hydroxyapatite is through compound hemostatic microballoon made from compound, solvent evaporation method；
Preferably, the compound hemostatic microballoon has the microsphere surface carrier of open-celled structure and naked by perforate
Expose and be enriched in the hydroxyapatite of the microsphere surface.
3. composite according to claim 2, it is characterised in that
The molecular weight of the compound hemostatic microballoon is 10000~500000, and grain diameter is 5~500 μm；Enter one
Preferably, the molecular weight of the compound hemostatic microballoon is 20000~50000, such as 30000~40000 to step；
Grain particle diameter is 50~350 μm, such as 150~250 μm, is specifically as follows 200 μm.
4. the composite according to claim any one of 1-3, it is characterised in that
The Biodegradable polyester refers to the polyester polymers with biodegradation character；
The preference of above-mentioned Biodegradable polyester can enumerate poly adipate succinic acid ester-poly terephthalic acid fourth
It is ethylene terephthalate copolymers, PHA, polyglycolic acid, poly butylene succinate, poly-epsilon-caprolactone, poly-
Succinic acid-butanediol ester-poly adipate succinic acid ester copolymer, poly butylene succinate-poly terephthalic acid fourth
Ethylene terephthalate copolymers, polydiethylene glycol sebacate-polybutylene terephthalate (PBT) copolymer, polylactide are (poly-
Lactic acid), PGA (polyglycolic acid), one kind in polycaprolactone and polylactide-co-glycolide
Or it is a variety of；Preferably polylactide；
The Biodegradable polyester monomer is that the raw material of the polyester can be obtained by polymerisation, for example may be used
Think the one or more in glycolide, lactide and caprolactone；
Preferably, the particle diameter of the hydroxyapatite is 10nm~10 μm；More preferably
10nm~200nm；More preferably 20~100nm；
Preferably, the compound hemostatic microballoon is the microballoon after degraded.
5. the system of the composite, particularly compound hemostatic microballoon any one of a kind of claim 1-4
Preparation Method, it is characterised in that comprise the following steps：
1) complex solution is prepared：Organic Biodegradable polyester and inorganic hydroxyapatite are answered
Close, obtained compound is dissolved in organic solvent, complex solution is obtained；
2) complex solution is prepared into by primary microballoon using solvent evaporation method；
3) the primary microballoon is degraded, obtains the compound hemostatic microballoon；
Preferably, organically the complex method of Biodegradable polyester and inorganic hydroxyapatite can be
Physics is compound and chemically composited；
The physics is compound to be referred to mix Biodegradable polyester and inorganic hydroxyapatite；
It is described chemically composited to refer to gather the open loop that hydroxyapatite and Biodegradable polyester are triggered by hydroxyl
Reaction is combined；It is more preferably chemically composited, more preferably it is combined using the method for chemical graft；
Preferably, chemically composited for example can be under the reaction condition of anhydrous and oxygen-free, by hydroxyapatite, third
Lactide and stannous octoate (SnOct2) and toluene add reaction tube in, capping pipe is reacted afterwards, example
Such as 12~120 hours (such as 48 hours) can be reacted under 60~180 DEG C (such as 120 DEG C)；Reaction is finished,
Separation product, for example, dissolved using solvent such as dichloromethane, and hexamethylene sedimentation obtains product；Product is at 45 DEG C
Vacuum drying chamber dry 72 hours after use；
Preferably, the mol ratio of stannous octoate and lactide can be (1:10)~(1:100), for example
(1:40)~(1:60), it is specifically as follows 1:50；The weight ratio of hydroxyapatite and lactide can be
(5:100)~(50:100) for example can be, 10:100,20:100,10:100；
Preferably, it for example can be with one by nano-grade hydroxy apatite and Biodegradable polyester that physics is compound
Determine weight ratio to be dispersed in organic solvent such as chloroform, be stirred vigorously, then sunk using solvent such as hexamethylene
Drop, compound is obtained after vacuum drying；Drying temperature can be 30~60 DEG C, and such as 45 DEG C, the time can be with
For 12~120 hours, such as 72 hours；
Preferably, the weight ratio of hydroxyapatite and Biodegradable polyester can be (5:100)~(50:100), example
Such as 10:100、20:100、30:100.
6. preparation method according to claim 5, it is characterised in that will be described using solvent evaporation method
The step of complex solution is prepared into primary microballoon includes：
21) complex solution is mixed with interior aqueous phase, emulsified for the first time, obtain first emulsified solution；
Preferably, the step 21) in complex solution is emulsified for the first time using high speed shear method, obtain
To first emulsified solution；
22) the first emulsified solution is mixed with outer aqueous phase, be stirred at room temperature, second emulsifying obtains oil-in-water
Solution, i.e., primary microballoon；
Preferably, the step 22) also include：Microballoon is taken out after being stirred at room temperature, with deionized water repeatedly from
Heart washing removes unnecessary NaOH, obtained after drying with good open-celled structure based on hydroxyapatite
Organo-mineral complexing hemostatic microsphere.
7. the preparation method according to claim 5 or 6, it is characterised in that the biological degradability gathers
Ester is the one or more in polylactide, PGA, polycaprolactone and polylactide-co-glycolide；
Preferably polylactide；
Preferably, the particle diameter of the hydroxyapatite is 10nm~10 μm；More preferably
10nm~200nm；More preferably 20~100nm.
8. the preparation method according to any one of claim 5-7, it is characterised in that
Step 1) in, the Biodegradable polyester and hydroxyapatite are according to weight (100：1)~(1:1)
Ratio be dissolved in the organic solvent of 5~40 times of weight, obtain complex solution；
Preferably, the ratio of the organic Biodegradable polyester and inorganic hydroxyapatite for example can be with
For 2:1；
Preferably, the organic solvent is dichloromethane；
Preferably, the interior aqueous phase and the outer aqueous phase are according to (0~1) by surfactant and water:50
G/mL is volume ratio of the weight with water of surfactant) it is well mixed what is obtained；
The surfactant is selected from the one or more in span60, span80, tween80 and PVA.
The volume ratio of the complex solution and interior aqueous phase is (1:1)~(20:1)；For example can be 4:1.
The volume ratio of the first emulsified solution and outer aqueous phase is (1:10)~(1:50).
9. the preparation method according to any one of claim 5-8, it is characterised in that
Step 3) in, the time is stirred at room temperature for 1~6 hour；
Preferably, the primary microballoon is degraded using the method for hydrolysis, aminolysis or enzyme degraded；
Preferably, the hydrolysis is carried out in alkaline solution；The alkaline solution can be KOH or NaOH
The aqueous solution；It is further preferred that the concentration of the KOH aqueous solution is 0.01~10M, the NaOH
The concentration of the aqueous solution is 0.01~2M；
Preferably, the aminolysis is carried out in the aqueous solution of amine；The amine is methylamine, ethylenediamine or triethylamine；
It is further preferred that the concentration of the aqueous solution of the methylamine, ethylenediamine or triethylamine is 0.2~10M；
Used in enzyme degraded in the form of the cushioning liquid or the aqueous solution of enzyme, it is preferable that the enzyme is
There is the enzyme of selectivity to Biodegradable polyester；It is further preferred that the cushioning liquid is slow for phosphate
Rush solution and/or tris cushioning liquid.
10. the composite any one of a kind of claim 1-4, particularly compound hemostatic microballoon are solidifying
Application in blood and/or hemostasis.
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| CN201610082226.XA CN107041964A (en) | 2016-02-05 | 2016-02-05 | Composite, preparation method and use |
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Cited By (5)
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| CN108114309A (en) * | 2018-01-02 | 2018-06-05 | 大连理工大学 | A kind of aldehydedodextrans/montmorillonite Composite rapid hemostatic material and preparation method thereof |
| CN113230447A (en) * | 2021-05-24 | 2021-08-10 | 河北工业大学 | Hemostatic repair material and preparation method thereof |
| CN113244441A (en) * | 2021-05-24 | 2021-08-13 | 河北工业大学 | Composite hemostatic repair material and preparation method thereof |
| CN113274954A (en) * | 2021-07-21 | 2021-08-20 | 北京德人健康科技有限公司 | Microsphere emulsification technology |
| CN113679877A (en) * | 2021-08-13 | 2021-11-23 | 中国科学院上海硅酸盐研究所 | Hydroxyapatite super-long nanowire hemostatic aerogel and preparation method and application thereof |
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| CN103319696A (en) * | 2012-03-23 | 2013-09-25 | 中国科学院化学研究所 | Hydroxyapatite/biodegradable polyester composite material and preparation method thereof |
| CN103768658A (en) * | 2012-10-18 | 2014-05-07 | 上海纳米技术及应用国家工程研究中心有限公司 | Hydroxyapatite-loading polylactic acid porous microsphere and preparation method thereof |
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| JP2004081739A (en) * | 2002-08-29 | 2004-03-18 | Mitsuru Akashi | Composition for hemostasis of hydroxy apatite polymer composite material |
| CN101590388A (en) * | 2009-06-18 | 2009-12-02 | 重庆文理学院 | A kind of preparation method of nano hydroxyapatite/polylactic acid composite microspheres |
| CN103319696A (en) * | 2012-03-23 | 2013-09-25 | 中国科学院化学研究所 | Hydroxyapatite/biodegradable polyester composite material and preparation method thereof |
| CN103768658A (en) * | 2012-10-18 | 2014-05-07 | 上海纳米技术及应用国家工程研究中心有限公司 | Hydroxyapatite-loading polylactic acid porous microsphere and preparation method thereof |
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| CN108114309A (en) * | 2018-01-02 | 2018-06-05 | 大连理工大学 | A kind of aldehydedodextrans/montmorillonite Composite rapid hemostatic material and preparation method thereof |
| CN113230447A (en) * | 2021-05-24 | 2021-08-10 | 河北工业大学 | Hemostatic repair material and preparation method thereof |
| CN113244441A (en) * | 2021-05-24 | 2021-08-13 | 河北工业大学 | Composite hemostatic repair material and preparation method thereof |
| CN113244441B (en) * | 2021-05-24 | 2022-03-15 | 河北工业大学 | Composite hemostatic repair material and preparation method thereof |
| CN113230447B (en) * | 2021-05-24 | 2022-04-08 | 河北工业大学 | Hemostatic repair material and preparation method thereof |
| CN113274954A (en) * | 2021-07-21 | 2021-08-20 | 北京德人健康科技有限公司 | Microsphere emulsification technology |
| CN113679877A (en) * | 2021-08-13 | 2021-11-23 | 中国科学院上海硅酸盐研究所 | Hydroxyapatite super-long nanowire hemostatic aerogel and preparation method and application thereof |
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