The anticoagulant methods of medical macromolecular materials or product surface
(1) technical field:
The present invention relates to the anti-freezing technologies of a kind of medical macromolecular materials or product surface.
(2) background technology:
With the medical material and device of contacting blood, as artificial blood vessel, artificial heart, artificial lung, mediated therapy guide wire,
Scaffold tube, intubation, isocon arteriovenous pressure-measuring pipe etc., oneself is widely used in modern medical service.These materials and device are usual
Mainly high molecular material is made, itself does not have anticoagulant characteristic or anticoagulation time is less than use.When blood with
Contact after, will produce a series of physiological reaction, such as absorption and the activation of blood platelet, the activating of complement, interior external source solidifies
The activation etc. of system, eventually leads to the formation of micro- bolt or thrombus.Therefore it must make entire patient's test tube of hepari when in use, make whole body
Blood cannot solidify, and thus cause while in operation and the potential danger of postoperative hemorrhage, oozing of blood, in some cases (such as wound, sheet
Bleed and needed the patient to stop blooding) it can not use at all.Therefore the research of medical high polymer anticoagulant material, whether from making in short term
It is required that being all very urgent for the requirement being especially used for a long time.The surfaces GBH heparin is started from Gott in 1963 et al.
Since change method, the research of domestic and international this respect achieves greater advance.A kind of improvement is described if patent 03116747.0
The coating solution and coating of biomedical devices surface anticoagulant performance.When contacting blood, heparin exists this kind of heparinnized materials
Material surface gradually release and caused by heparin microenvironment, it is good anti-that certain heparin rate of release can be such that high molecular material has
Solidifying property.
Heparin is a kind of water-soluble aminopolysaccharide sulfate, and molecular weight is 2000 or so, and chain link unit is by glucose
Amine sulfonic acid, glucuronic acid and Chinese mugwort society sugar sulphur aldehydic acid etc. are formed, it is inhibited by being combined with Antithrombin III (AT-III)
The activity of serine protease prevents coagulation process in blood clotting alternative pathway, has strong inhibition blood coagulation in vivo
The effect of activation, long-term clinical application prove that anticoagulant effect is good, using appropriate safe and reliable.
No matter in vivo or external heparin is, all has blood coagulation resisting function, is used clinically for prevention thrombosis, various
Anti-freezing processing during disseminated intravascular coagulation caused by reason, extracorporal circulatory system etc. etc..In order to avoid systemic injection heparin
The harm brought, while increasing the biocompatibility of material, heparin is fixed on by polymer surface by certain method,
It can obtain good anticoagulant effect.This heparinized surface can reduce after extracorporal circulatory system Complement C_3 in blood, the level of C4,
Blood platelet, fibrinogen, lipoprotein and other macro-molecular proteins can be prevented in the adherency of material surface simultaneously, to have
Effect improves the blood compatibility of material surface, thus heparin is fixed on polymer surface with improve its anticoagulant property and
Its persistence is the important channel for the anticoagulant property for improving material.At present the emphasis of material surface test tube of hepari focus primarily on how
Improve the bioactivity and its persistence of the concentration and heparin of material surface test tube of hepari.The test tube of hepari of polymer surface, one
As have two kinds of physisorphtion and chemical bonding processes.The former combination is not too strong, but the conformation of heparin can be kept, activity compared with
Height, but effective anticoagulation time is shorter;And the combination of the latter is stablized, but the conformation of heparin is not easy to keep, and the biology of heparin is living
Relatively low, material anticoagulant property the improvement of property is not apparent.Current solution is usually first to connect compliance in material surface
Good spacerarm, then heparin is fixed on spacerarm, polyoxyethylene is most common spacerarm.Heparin can be both maintained in this way
Native conformation and bioactivity, and can make heparin material surface combine stablize.But existing test tube of hepari anticoagulant material, one
Aspect is that complex process is difficult to produce, and cost is higher, is unsuitable for being widely popularized;On the other hand original anti-freezing curing process
It can play the shorter anti-freezing time, anti-freezing material is only used for the material compared with the short operation time such as plasma composition acquisition, haemodialysis
Expect anti-freezing, and for need indwelling in vivo the long period the case where can not meet if chemotherapy of tumors deep intravenous integrated catheter etc.
It needs, it is therefore desirable to grope condition, by anti-freezing time lengthening.By experiment, extends hardening time, make heparin in high molecular material
Upper absorption more securely, stand washing away for blood flow, it is small to reach the anti-freezing material direct contact ex vivo blood anticoagulant time 14
When more than.
(3) invention content:
It is an object of the present invention to provide medical macromolecular materials or the anticoagulant methods of product surface, it can solve the prior art
Deficiency, by synthesize the good heparin complexes of anticoagulation function, be dissolved in that coating fluid is made in suitable organic solvent,
Medical macromolecular materials surface is coated on using appropriate method, using curing process, it is lasting to be allowed to anticoagulant functions, through dry
Shady place is placed after dry to retain for use;Present invention operation is simple, environmental protection, safety, cost are relatively low, and amplification is suitable for be gone forward side by side professional etiquette modelling
Production, does not influence the physicochemical property for being applied material, obtained material surface anticoagulation function is excellent after being coated with present invention process
It is good and can keep stablize.
Technical scheme of the present invention:The anticoagulant methods of medical macromolecular materials or product surface, include the following steps:(1)
The preparation of heparin complexes;(2) preparation of coating fluid;(3) it is coated with;(4) curing process;It is characterized in that in the step (4)
The surface of medical macromolecular materials contact blood is dipped in dual-functional group curing agent and is cured at 30~60 DEG C, hardening time
It is 60~100 minutes.
The preparation method of step (1) heparin complexes is:
1) heparin sodium is dissolved in purified water or distilled water, a concentration of 1%~10% (g/ml) solution is made into, by quaternary ammonium salt
It is gradually added dropwise in above-mentioned solution, until there is white flock precipitate;The reaction was continued 5~30 minutes, is allowed to fully react and divide
Layer is apparent;
2) it filters, obtains white precipitate, precipitation is shredded and fully impregnated with purified water or distilled water, be washed till white repeatedly
Precipitation start to unite and noresidue quaternary ammonium salt until, obtain white or light yellow heparin complexes;Finally it is put in vacuum desiccator
In nature or be dried under reduced pressure to constant weight.
The method of the preparation of step (2) coating fluid is:
1) according to the characteristics of variety classes medical macromolecular materials and by heparin complexes be dissolved in single organic solvent or its
In mixed organic solvents, it is made into coating solution;
2) it is coated with a concentration of 0.1%~10% (g/ml) of solution.
The method of the step (3) coating is:
It will be coated with solution, medical macromolecular materials surface is coated on, is taken out after 10 seconds~3 hours, 30~50 DEG C of hot wind
Drying, it is reversed after 1~5 hour to be coated with once with same method again.
The method of step (4) curing process is:
1) bifunctional group curative concentration is 0.1%~1% (ml/ml);
2) surface of medical macromolecular materials contact blood is dipped in dual-functional group curing agent and is cured;
3) clean coating surface with purified water or distilled water to remove unreacted dual-functional group curing agent, naturally dry or
Drying, obtains the medical macromolecular materials of test tube of hepari.
The medical macromolecular materials are:Polyvinyl chloride, polyethylene, polyoxyethylene, makrolon, polypropylene, polyurethane,
Polystyrene, polytetrafluoroethylene (PTFE), cellulose derivative, polysulfones, polyether sulfone or silicon rubber.
Organic solvent used in the dissolving heparin complexes is chloroform, trichloroethanes, dichloroethanes, dichloromethane
Two or more mixing in alkane, methanol, ethyl alcohol or more solvent.
The present invention is advantageous in that:Present invention operation is simple, environmental protection, effect safety, cost are relatively low, and amplification is suitable for be gone forward side by side
Row large-scale production;Original anti-freezing curing process can only play the shorter anti-freezing time, and anti-freezing material is only used for plasma composition
Acquisition, haemodialysis etc. compared with the short operation time material anti-freezing, and for need indwelling in vivo the long period the case where as swollen
Tumor chemotherapy deep intravenous integrated catheter etc. then can not meet needs, it is therefore desirable to grope condition, by anti-freezing time lengthening.By reality
It tests, extends hardening time, so that heparin is adsorbed on high molecular material more secured, stand washing away for blood flow, it is anti-to reach
14 hours direct contact ex vivo blood anticoagulant time of gel material or more, and suitable for common a variety of high molecular materials;With this
Do not influence to be applied the physicochemical property of material after invented technology coating, obtained material and product anticoagulation function are excellent and can protect
It is fixed to keep steady.
Various medical macromolecular materials include:Polyvinyl chloride, polyurethane, the anticoagulant effect of silicon rubber are best;And polyethylene,
Polyoxyethylene, makrolon, polypropylene, polystyrene, polytetrafluoroethylene (PTFE), cellulose derivative, polysulfones, polyether sulfone parent's bolt are compound
Also there are preferable anticoagulant efficacy, general nature that can meet requirement.
(4) specific implementation mode:
Embodiment l:The anticoagulant methods of medical macromolecular materials or product surface, include the following steps:
(1) preparation of heparin-benzalkonium bromide complex compound:
1) heparin sodium 0.1g is dissolved in 10ml purified waters or distilled water;
2) benzalkonium bromide solution is made into the concentration of 5% (ml/ml) with purified water;
3) 5% benzalkonium bromide solution is gradually added dropwise in above-mentioned heparin sodium aqua, until there is white precipitate suspended matter
Until.The reaction was continued 5 minutes, is allowed to fully react and white precipitate and solution layering are apparent.
4) it uses G2 funnels to filter again, obtains white precipitate.White precipitate purified water or distilled water, which are fully ground, washes immersion, instead
After backwashing to white precipitate start to unite and noresidue quaternary ammonium salt until, obtain being similar to fragrant sugared shape white or the complexing of light yellow heparin
Object.It is finally put in nature in vacuum desiccator or is dried under reduced pressure to constant weight.Complex compound can be also made in other quaternary ammonium salts in this way
Anti-freezing for medical macromolecular materials.
(2) it is coated with and cures medical polyvinyl (PVC) and manage:
1) preparation of coating fluid:
Heparin quaternary ammonium complex 0.1g described in step (1) is dissolved in 100ml chloroform solns, is fully dissolved
The coating solution of water white transparency is obtained afterwards.
2) it is coated with:
Formula is flowed through into the coating fluid prepared use in 100 grades of environment purifications and is coated on doctor with the method that immersion type is combined
With pvc pipe surface, take out, dried under room temperature or with 30 DEG C of hot blast dryings after 10 seconds, after 1~5 hour it is reversed use again it is same
Method coating is primary, and medical PVC pipe surface forms stable heparin coating, is dried under room temperature.
3) curing process:
1. by curing agent bifunctional group reagent glutaraldehyde, the concentration of 0.1% (ml/ml) is made into purified water.
2. above-mentioned coated medical PVC pipe is soaked in bifunctional group reagent, and cure at 30 DEG C, cures
Time is 60 minutes, forms cross-linked heparin polymer coating.Unreacted bifunctional group reagent finally is cleaned up with purified water,
After being dried under room temperature, the medical PVC pipe of test tube of hepari is obtained.
Embodiment 2:It is coated with and cures medical makrolon (PC) pipe:
1) preparation of coating fluid:
By the heparin quaternary ammonium complex 10g described in 1 step of embodiment (1), it is dissolved in bis- chloroethene of 40ml methanol and 60ml
In alkane solution, fully the coating solution of water white transparency is obtained after dissolving.
2) it is coated with:
The coating solution prepared is poured into medical PC pipes in 100 grades of environment, impregnate 3 hours, be allowed to surface formed it is stable
Heparin coating takes out, naturally dry.
3) curing process:
1. by curing agent bifunctional group reagent glutaraldehyde, the concentration of 1% (ml/ml) is made into purified water.
2. above-mentioned coated medical PC pipes are soaked in bifunctional group reagent, and cure at 60 DEG C, when solidification
Between be 100 minutes, formed cross-linked heparin polymer coating.Unreacted bifunctional group reagent finally is cleaned up with purified water,
After natural drying, the medical PC pipes of test tube of hepari are obtained.
Embodiment 3:Coating and solidification medical grade silicon rubber (SR) are managed:
1) preparation of coating fluid:
Heparin quaternary ammonium complex 1g described in 1 step of embodiment (1) is dissolved in 100ml chloroform solns, is filled
The coating solution of water white transparency is obtained after dividing dissolving.
2) it is coated with:
Formula is flowed through into the coating fluid prepared use in 100 grades of environment purifications and is coated on doctor with the method that immersion type is combined
It with SR pipe surfaces, takes out after forty minutes, naturally dry or drying, it is reversed after 1~5 hour to be coated with one with same method again
Secondary, medical SR pipe surfaces form stable heparin coating, naturally dry.
3) curing process:
1. by curing agent bifunctional group reagent glutaraldehyde, the concentration of 0.5% (ml/ml) is made into purified water.
2. above-mentioned coated medical SR pipes are soaked in bifunctional group reagent, and cure at 30 DEG C, cures
Time is 80 minutes, forms cross-linked heparin polymer coating.Unreacted bifunctional group reagent finally is cleaned up with purified water,
After natural drying, the medical SR pipes of test tube of hepari are obtained.
Embodiment 4:The anticoagulant methods of medical macromolecular materials or product surface, include the following steps:
(1) preparation of heparin-benzalkonium chloride complex compound:
1) heparin sodium 0.1g is dissolved in 10ml purified waters or distilled water;
2) Benza is made into the concentration of 5% (ml/ml) with purified water;
3) 5% Benza is gradually added dropwise in above-mentioned heparin sodium aqua, until there is white precipitate suspended matter
Until.The reaction was continued 5 minutes, is allowed to fully react and white precipitate and solution layering are apparent.
4) it uses G2 funnels to filter again, obtains white precipitate.White precipitate purified water or distilled water, which are fully ground, washes immersion, instead
After backwashing to white precipitate start to unite and noresidue quaternary ammonium salt until, obtain being similar to fragrant sugared shape white or the complexing of light yellow heparin
Object.It is finally put in nature in vacuum desiccator or is dried under reduced pressure to constant weight.Complex compound can be also made in other quaternary ammonium salts in this way
Anti-freezing for medical macromolecular materials.
(2) it is coated with and cures medical polyvinyl (PVC) and manage:
1) preparation of coating fluid:
Heparin quaternary ammonium complex 0.1g described in step (1) is dissolved in 100ml chloroform solns, is fully dissolved
The coating solution of water white transparency is obtained afterwards.
2) it is coated with:
Formula is flowed through into the coating fluid prepared use in 100 grades of environment purifications and is coated on doctor with the method that immersion type is combined
With pvc pipe surface, take out, dried under room temperature or with 30 DEG C of hot blast dryings after 10 seconds, after 1~5 hour it is reversed use again it is same
Method coating is primary, and medical PVC pipe surface forms stable heparin coating, is dried under room temperature.
3) curing process:
1. by curing agent bifunctional group reagent glutaraldehyde, the concentration of 0.1% (ml/ml) is made into purified water.
2. above-mentioned coated medical PVC pipe is soaked in bifunctional group reagent, and cure at 30 DEG C, cures
Time is 60 minutes, forms cross-linked heparin polymer coating.Unreacted bifunctional group reagent finally is cleaned up with purified water,
After being dried under room temperature, the medical PVC pipe of test tube of hepari is obtained.
Embodiment 5:It is coated with and cures medical makrolon (PC) pipe:
1) preparation of coating fluid:
By the heparin quaternary ammonium complex 10g described in 4 step of embodiment (1), it is dissolved in bis- chloroethene of 40ml methanol and 60ml
In alkane solution, fully the coating solution of water white transparency is obtained after dissolving.
2) it is coated with:
The coating solution prepared is poured into medical PC pipes in 100 grades of environment, impregnate 3 hours, be allowed to surface formed it is stable
Heparin coating takes out, naturally dry.
3) curing process:
1. by curing agent bifunctional group reagent glutaraldehyde, the concentration of 1% (ml/ml) is made into purified water.
2. above-mentioned coated medical PC pipes are soaked in bifunctional group reagent, and cure at 60 DEG C, when solidification
Between be 100 minutes, formed cross-linked heparin polymer coating.Unreacted bifunctional group reagent finally is cleaned up with purified water,
After natural drying, the medical PC pipes of test tube of hepari are obtained.
Embodiment 6:Coating and solidification medical grade silicon rubber (SR) are managed:
1) preparation of coating fluid:
Heparin quaternary ammonium complex 1g described in 4 step of embodiment (1) is dissolved in 100ml chloroform solns, is filled
The coating solution of water white transparency is obtained after dividing dissolving.
2) it is coated with:
Formula is flowed through into the coating fluid prepared use in 100 grades of environment purifications and is coated on doctor with the method that immersion type is combined
It with SR pipe surfaces, takes out after forty minutes, naturally dry or drying, it is reversed after 1~5 hour to be coated with one with same method again
Secondary, medical SR pipe surfaces form stable heparin coating, naturally dry.
3) curing process:
1. by curing agent bifunctional group reagent glutaraldehyde, the concentration of 0.5% (ml/ml) is made into purified water.
2. above-mentioned coated medical SR pipes are soaked in bifunctional group reagent, and cure at 30 DEG C, cures
Time is 80 minutes, forms cross-linked heparin polymer coating.Unreacted bifunctional group reagent finally is cleaned up with purified water,
After natural drying, the medical SR pipes of test tube of hepari are obtained.
Technique effect:The test of quiescent anticoagulated courageous and upright energy
The main method of evaluation medical macromolecular materials anticoagulation function can be divided into external, internal and halfbody at present
Interior equal three categories.GB/T16886.1-2001 and GB/T16886.4-2003 give BiologicalEvaluationofMedicalDevice in China
The description of some property summarized.We study and select extracorporeal blood contact method treated detecting test tube of hepari and is medical herein
The anticoagulation function of high molecular material.
So-called extracorporeal blood contact method refers to that blood is directly extracted out blood from the heart of experimental animal, by its with wait seeing
It examines material to contact in some way after a certain period of time, then influence of the observation detected materials to blood clotting in vitro.Specific behaviour
It is as step:
(1) selection of rabbit:Adult, health, 2.5~4.0Kg;
(2) blood collection needles passivation and silicidation;
(3) syringe needle after passivation and silicidation is properly inserted rabbit ventricle, obtain new fresh rabbit blood injection embodiment 3,
The 5 treated medical macromolecular materials pipe of embodiment 4 and embodiment, is put into 37 ± 1 DEG C of water-baths (or incubator), immediately
Start to clock, stand 15 minutes, respectively take seen if there is in a bit of clean beaker for being put into and fill 0.9%NaCl blood point, clot,
Thrombus occurs, and to have blank control.Hereafter 30 minutes every (or 60 minutes) observation is primary, is until small blood point occurs in blood
Only.Record final anticoagulation time at this time.With the polyvinyl chloride of heparin quaternary ammonium complex anti-freezing, anti-it can be seen from following table
The anti-freezing time of cohesion carbonic ester and silicone rubber tube was all up by 14 hours, and it is existing just to occur cohesion to 15 hours (900min)
As.
Time |
Anti-freezing polyvinyl chloride |
Anti-freezing makrolon |
Anti-freezing silicone rubber tube |
The non-anti-freezing of blank |
15min |
- |
- |
- |
- |
30min |
- |
- |
- |
+ |
60min |
- |
- |
- |
+ |
120mi |
- |
- |
- |
+ |
180mi |
- |
- |
- |
+ |
240mi |
- |
- |
- |
+ |
300mi |
- |
- |
- |
+ |
360mi |
- |
- |
- |
+ |
420mi |
- |
- |
- |
+ |
480mi |
- |
- |
- |
+ |
540mi |
- |
- |
- |
+ |
600mi |
- |
- |
- |
+ |
660mi |
- |
- |
- |
+ |
720mi |
- |
- |
- |
+ |
780mi |
- |
- |
- |
+ |
840mi |
- |
- |
- |
+ |
900mi |
+ |
+ |
+ |
+ |
960mi |
+ |
+ |
+ |
+ |
Note:"-" indicates that no blood point, clot, thrombus occur in table, and blood point, clot, thrombus occurs in "+" expression.