CN1978492A - Polycaprolactone-polyethylene glycol block copolymer, and its preparing method and use - Google Patents
Polycaprolactone-polyethylene glycol block copolymer, and its preparing method and use Download PDFInfo
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- CN1978492A CN1978492A CNA2006100979864A CN200610097986A CN1978492A CN 1978492 A CN1978492 A CN 1978492A CN A2006100979864 A CNA2006100979864 A CN A2006100979864A CN 200610097986 A CN200610097986 A CN 200610097986A CN 1978492 A CN1978492 A CN 1978492A
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- peo
- pcl
- polycaprolactone
- polyethylene glycol
- alkyl
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- 238000006243 chemical reaction Methods 0.000 claims description 36
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- Materials For Medical Uses (AREA)
Abstract
This invention provides the periodic copolymer PCL-PEO-R which was polymerized with poly-epsilon-caprolactone and polyethylene glycol. The polymerization degree of PCL segment is between 10 and 1000, and the corresponding molecular weight is between 1000 and 100000; the polymerization degree of PEO segment is between 10 and 100, and the corresponding molecular weight is between 400 and 5000; the interval group between tertiary amine N and PEO is the alkyl made up of 2-10 carbon atoms, and the selective preference number of carbon atom is 2-4. The other two alkyls on the atom of tertiary amine N may be the same either the different methyl or ethyl. The alkyls which were used to composite phosphorylcholine were made up of the liner chain or the branched chain, and the saturated or the unsaturated alkyls with 1-20 carbon atoms. This invention also provides the preparation of the interpolymer, as well as its application in the preparation of biology medical material.
Description
One, technical field
The present invention relates to a kind of polycaprolactone-polyethylene glycol block copolymer that has the Phosphorylcholine end group, the preparation method of this multipolymer and the application in the biocompatibility modification of polymer surface thereof belong to biomedical materials field.
Two, background technology
Develop rapidly along with biomedical engineering technology, in a large number with the artificial organs of macromolecular material preparation with medicine equipment begins to come into one's own and there have part to be used for to be clinical, especially in the field relevant with blood circulation, progressively obtain further investigation and application such as artificial blood vessel, artificial valve and stent etc., but its effect but often seems not very good because of forming thrombus.Thereby, seek a kind of both had good mechanical mechanical property, processing characteristics, ageing-resistant performance etc., the material that has simultaneously good blood and histocompatibility has again become the problem that receives much attention in this field, but it is very few to have both the ideal material of above-mentioned two kinds of performances.
A kind of material is with after organism contacts, the immunity system of organism can be made the identification and the judgement of a series of instincts, the ideal state is through the fusion of realization after the of short duration rejection with organism, often cause acute tissue necrosis and chronic canceration but most cases is next, a kind of result that can accept for the people is the encapsulated film parcel of implant, with organism long-term co-existence, this also is a present biomedical sector target in power to bio-medical material then.And when material directly contacts with blood, just the absorption of plasma proteins (albumin, sphaeroprotein, Fibrinogen etc.) at first appears at material surface in several seconds, thrombocyte begins to adhere to, assembles, is out of shape subsequently, and blood coagulation system, fibrinolytic system are activated, and finally form thrombus.More than all these identifications with judge that often based on the surface properties of material, especially aspect the blood compatibility directly related with blood, the surface properties of material is the deciding factor whether a kind of material has blood compatibility.Thereby, optimize the material surface performance and become a kind of material that makes both to keep original mechanical property, processing characteristics, ageing-resistant performance, and satisfy the quick of tissue/blood compatibility requirement simultaneously and effective means.This optimization comprises two kinds of methods: the one, utilize the principle of surface adsorption, and will have the material of tissue/blood compatibility or group and be coated to material surface and realize modification; Another kind method then is to utilize the chemical graft principle to utilize chemical bond-linking to receive material surface the material of required tissue/blood compatibility or group to realize modification.
The surface (comprising chemical constitution and physical condition) that the surface properties that changes a kind of material will realize material in fact exactly is differential with material body, this difference can realize with the method that applies simply, smear one deck oil simply such as needing only at a hydrophilic material surface, utilize the Intermolecular Forces between oil and the material that oil is adsorbed on material surface, just can realize temporary transient hydrophobic of material surface.The material modified surface of surface coating process makes it have tissue/blood compatibility and has just utilized this principle, the benefit of this method maximum just is simply, quick and be not obvious especially to the selectivity of material body, thereby in some temporary application, be developed.But owing to be coated in the material of material surface and the balance that the adsorption between the material body always exists absorption and desorb, when the material surface after the modification runs into different environment, tend to take place desorb, even only along with the prolongation of time, adsorbed material also can come off gradually, thereby influenced the effectively lasting of material surface character, this also is the shortcoming and defect of this method maximum.These drawbacks limit this method in the application that needs the occasion that the long period plays a role.
The method of grafting modification material surface has then just in time overcome the shortcoming of surface-coated method modification lastingly, can utilize chemical bond to be securely fixed in material surface material or group, thereby realize permanent modification material surface with tissue/blood compatibility.In the past few decades, the research report that a large amount of relevant this respects have been arranged, related material comprises various macromolecular materials such as polyethylene (PE), polypropylene (PP), polymethylmethacrylate (PMMA), polyacrylonitrile (PAN), polyvinyl chloride (PVC), urethane (PU), polyester (PET), polyethersulfone (PES), polypyrrole (PPy), silicon rubber, Mierocrystalline cellulose, chitosan, purpose be nothing but make the material surface inerting, at imitation biochemistry of material surface load anticoagulative substance and material surface etc.
For most macromolecular materials, its surface for chemical reaction often show and torpescence or even complete inert, to in the material surface grafting, help organizing with the material or the group of blood compatibility and be not easy, reach such purpose, often need at least three steps: 1, produce and can participate in the Activity of Chemical Reaction point at material surface, but as producing free radical or corresponding reactive group occurring.This step often needs the condition of comparison fierceness, and known method comprises methods such as ozonize, glow discharge, laser-induced thermal etching, high-energy irradiation, Low Temperature Plasma Treating.These are handled when producing required active site, can impact material body character more or less; 2, grafting interval material or group on the active site that the first step produces.On the active site that the first step reaction produces, if direct required active substance such as the heparin of grafting, phosphatide, protein etc., then often, the conformation transition of active substance is difficult to play a role owing to being restricted, thereby need between active substance and active site, connect spacer again with certain-length, such spacer guarantees firm connection the between active substance and the material activity point on the one hand, often need it to have certain wetting ability on the other hand, so that under the organism environment, can freely stretch and move and guarantee that its terminal active group has enough conformations and adjusts degree of freedom, thereby guarantee the performance of its performance, normally used spacer is the wetting ability biocompatibility macromolecule with certain molecular weight, as polyoxyethylene glycol (PEG/PEO), polyvinylpyrrolidone (PVP) etc.; 3, at the end of spacer, required biological affinity material of the final grafting of after chemical reaction such as heparin, phosphatide, protein etc. again.
Finally, the chemical graft polymer surface needs three step chemical reactions at least, and, since the specificity of various materials, required step even more is more loaded down with trivial details.
Comparison surface applies and the method on two kinds of material modified surfaces of chemical graft, and surface coating process has simple, fast advantage, but to the persistence deficiency of material surface modifying; And the chemical graft method can realize persistent material surface modifying, but process is loaded down with trivial details and universality is poor, almost needs the material of modification all to need a series of specific chemical reactions to realize to each.
At the problems referred to above, the present invention proposes will connect the flexible polymer of functional group by self-assembly with a kind of mode of self-assembly, " hammer into " material that needs modification as " nailing ", by selecting suitable " nail " material, the firm connection of functional group at material surface both was provided, the simple, fast modification mode that all is suitable for for multiple material was provided again.This method can be with model illustrative shown in Figure 1.Wherein 1 is the functional group that connects on the block polymer, is to have biocompatible substances, as materials such as phosphatide, heparin, protein; The 2nd, in the block polymer one section, be characterized in having biocompatibility and in the water surrounding of organism, be flexible, thereby the freedom of assurance function group is connected and can come off from the material surface that is modified by the assurance function group by the chemical bond with " nail "; The 3rd, another section in the block polymer, be so-called in the model " nail ", be the amphipathic nature polyalcohol with biocompatibility (Bio-compatible) and polymer phase capacitive (Polymer-compatible), 2,3 by chemical bond connection formation block polymer; The 4th, the macromolecular material that is modified.
The key that realizes such model is block polymer and preparation method thereof and the application method in the modification of macromolecular material biocompatibility that has the function end group.Block polymer involved in the present invention is the bi-block copolymer that is made of-polycaprolactone (PCL) and polyoxyethylene glycol (PEO), the molecular weight of PCL section is that 1000-100000 does not wait, the molecular weight of PEO section is that 400-5000 does not wait, function end group R is the alkyl phosphorylcholine with different structure, and the block polymer that has a function end group can be remembered and makes PCL-PEO-R.
The preparation of PCL-PEO-R is rationally improved the synthetic method of known PCL, PEO, alkyl phosphorylcholine and is made up, and carries out the chemical reaction synthetic of twice anionic ring-opening polymerization and end group by selecting specific initiator.
Utilize the PCL-PEO-R block polymer can be by with the blend of different macromolecular materials or macromolecular material is carried out surface treatment carry out to the modification of macromolecular material.
The present invention promptly discloses a kind of like this block polymer and preparation method thereof, also discloses simultaneously to utilize the PCL-PEO-R block polymer that the biocompatibility modification of macromolecular material is used.
Three, summary of the invention
1, goal of the invention: the objective of the invention is to disclose a kind of block polymer PCL-PEO-R that has the alkyl phosphorylcholine end group, the molecular weight of PCL section is that 1000-100000 does not wait, the molecular weight of PEO section is that 400-5000 does not wait, and function end group R is the alkyl phosphorylcholine base with different structure.
Another object of the present invention is to disclose the above-mentioned preparation method who has the block polymer PCL-PEO-R of alkyl phosphorylcholine end group, this building-up process is rationally improved the synthetic method of known PCL, PEO, alkyl phosphorylcholine and is made up, and carries out the chemical reaction synthetic of twice anionic ring-opening polymerization and end group by selecting specific initiator.
Another object of the present invention is a method of openly utilizing the above-mentioned block polymer PCL-PEO-R that has the alkyl phosphorylcholine end group that multiple macromolecular material is carried out the biocompatible surfaces modification, and this method of modifying is by PCL-PEO-R being carried out blend with different macromolecular material or surface treatment is carried out.
2, technical scheme: purpose of the present invention can reach by following measure.
The block polymer PCL-PEO-R that has the alkyl phosphorylcholine end group disclosed in this invention has structural formula as follows.Wherein, the PCL segmental polymerization degree represents that with m between 10-1000, the about 1000-100000 of corresponding molecular weight does not wait; The PEO segmental polymerization degree represents that with n between 10-100, the about 400-5000 of corresponding molecular weight does not wait; The alkyl that atom of tertiary amine N and PEO spacer groups are made up of 2-10 carbon atom, preferred carbonatoms is 2-4; Two other alkyl on the atom of tertiary amine N can be identical or different methyl or ethyl; Saturated or the undersaturated alkyl alcohol of the straight or branched that the alkyl alcohol that constitutes alkyl phosphorylcholine is made up of 1-20 carbon atom wherein can also have one or more hydroxyls, halogen groups such as (Cl, Br, I) as required.
m＝10-1000；n＝10-100；x＝2-10；
R
1，R
2＝CH
3，CH
2CH
3
R
3＝CH
3，(CH
2)
yCH
3(y＝1-20)
The synthetic method that has the block polymer PCL-PEO-R of alkyl phosphorylcholine end group disclosed in this invention comprises three steps: the first step: a synthetic terminal hydroxy group, and the other end has the PEO of tertiary amine group; Second step: at the synthetic PCL segment of hydroxyl one end of PEO; The 3rd step: utilize the chemical reaction of tertiary amine group to connect the alkyl phosphorylcholine group that needs, synthetic route is shown below.
Detailed synthesis step is described as follows:
The first step: a synthetic terminal hydroxy group, the other end has the PEO of tertiary amine group.
Oxyethane ring opening synthesis PEO under the negatively charged ion effect is a technique known.It is initiator that the present invention selects the special alkyl alcohol that has tertiary amine group for use, the PEO of ring opening synthesis one terminal hydroxy group, an end tertiary amine groups under the negatively charged ion effect.Building-up process is will contain anionic initiator reaction such as the alkyl alcohol of tertiary amine and sodium Metal 99.5, KOH earlier through careful exsiccant and slough water to make corresponding alkoxide, add in the autoclave then, carefully remove the airtight and oxyethane of input requirement once or several times behind oxygen and the water, react to oxyethane consumption at 60-120 ℃ and to finish, take out adding acid neutralization, obtain the PEO of a terminal hydroxy group, an end tertiary amine groups after making with extra care.With infrared spectra (FTIR), nuclear magnetic resonance spectrum (NMR), gel permeation chromatography methods such as (GPC) resulting product is characterized.
Second step: the PCL segment in the synthetic PCL-PEO-R block polymer.
The PEO of the first step preparation is mixed with the careful dried 6-caprolactone of the warp of requirement in the adding tube sealing, add a small amount of stannous octoate catalyst, fill N repeatedly
2, vacuumize 3 times after at vacuum lower seal tube sealing, tube sealing is put 140 ℃ of down reaction coolings after at least 72 hours, take out and be dissolved in the chloroform solvent, splash into then and precipitate in the cold isopropanol solvent, repeat said process and obtain the PCL-PEO block polymer after once.With infrared spectra (FTIR), nuclear magnetic resonance spectrum (NMR), gel permeation chromatography methods such as (GPC) resulting product is characterized.
The 3rd step: the chemical reaction of tertiary amine group connects the alkyl phosphorylcholine group that needs.
Be being connected of alkyl phosphorylcholine group and PCL-PEO block polymer to utilize the tertiary amine ring-opening reaction of alkoxyl group oxygen phosphorus heterocycle alkane and PEO end to make.Alkoxyl group oxygen phosphorus heterocycle alkane needs synthetic according to technique known in advance, and its route is with glycol and PCl
3Reaction obtains the chlorodioxin phosphorus heterocycle, obtains chlorination oxo dioxy phosphorus heterocycle through dioxygen oxidation, is reflected at the saturated or unsaturated alkyl that has or do not have hydroxyl or halogen is pure that dehydrochlorination obtains alkoxyl group oxygen phosphorus heterocycle alkane in the alkaline environment again.After determining structure, methods such as FTIR, NMR in the organic solvent of room temperature or slightly heating, react 1 day time to 1 week with PCL-PEO, add precipitation agent and be settled out product, and remove unreacted alkoxyl group oxygen phosphorus heterocycle alkane through the solvent repetitive scrubbing, obtain the block polymer PCL-PEO-R product that target has the alkyl phosphorylcholine end group.With infrared spectra (FTIR), nuclear magnetic resonance spectrum (NMR), gel permeation chromatography methods such as (GPC) resulting product is characterized.
Disclosed by the inventionly utilize the above-mentioned block polymer PCL-PEO-R that has the alkyl phosphorylcholine end group, comprise with PCL-PEO-R and macromolecular material blend processing or with macromolecular material and in PCL-PEO-R solution, adsorb, apply and carry out through thermal treatment to the method that multiple macromolecular material carries out the biocompatible surfaces modification.The macromolecular material that can be used for modification comprises urethane, polyolefine such as polyvinyl chloride, polyester such as polycaprolactone, natural polymer such as Mierocrystalline cellulose etc.Corresponding blend operation can be adopted known blend means, carries out as methods such as melt-processed, kneading at a high speed, solution blendings; Surface treatment then can desolvate the volatilization behind the polymer surface of the solution spraying of PCL-PEO-R and obtain through thermal treatment, perhaps macromolecular material is immersed in the PCL-PEO-E solution for some time to take out after drying and finish through thermal treatment.Resulting macromolecular material characterizes through means such as surface protein absorption, mechanical property measurements.
3, beneficial effect: block polymer PCL-PEO-R that has an alkyl phosphorylcholine end group disclosed by the invention and preparation method and the method that this polymkeric substance is used for macromolecule material surface modification can be applied in the tissue/blood compatibility consistency modification field of bio-medical material are different from chemical graft and the directly painting method mentioned in the preamble.Advantage of the present invention is: PCL segment and multiple macromolecular material have good consistency in (1) PCL-PEO-R block polymer, are again a kind of bio-medical materials of slow degraded simultaneously; The PEO segment then is the bio-medical material that generally adopts; Phosphorylcholine is the material that itself just exists in the organism, and the introducing of alkyl phosphorylcholine group can further strengthen the performance of PCL-PEO polymkeric substance aspect tissue/blood compatibility; Three kinds of compounds all are the materials with excellent biological compatibility, can guarantee the biocompatibility of material, help final application.(2) utilize with a kind of this block polymer and can realize surface modification to multiple macromolecular material having tangible universality, avoided macromolecular material is carried out the loaded down with trivial details chemical reaction step of carrying out according to the differing materials needs in the surface modification.(3) the surface coating process modified polymer material surface similar techniques with common is the same, utilizes PCL-PEO-R block polymer of the present invention, can realize the modification to material requested simply, quickly, reduces corresponding material produce cost.(4) utilize the good consistency that a part of segment and multiple macromolecular material have simultaneously in this block polymer, guarantee that it " hammers into " polymer surface as " nail ", be unlikely to come off at short notice and lose tissue/blood compatibility that modification is given, satisfy the demand of association area.
Four, description of drawings
Fig. 1 is that the segmented copolymer that has the function end group carries out surface biological consistency modification model to macromolecular material.Wherein 1 is the functional group that connects on the block polymer; The 2nd, in the block polymer one section; The 3rd, another section in the block polymer, 2,3 by chemical bond connection formation block polymer; The 4th, the macromolecular material that is modified.
Fig. 2 is the gel permeation chromatography figure of PEO, PCL-PEO.
Fig. 3 is PCL-PEO-R
31The p-NMR spectrogram.
Five, embodiment
The present invention is further illustrated below in conjunction with embodiment, but the description of embodiment does not produce any restriction to protection of the present invention.
1, PEO section Alpha-hydroxy-ω-dimethylamino Soxylat A 25-7 synthetic among the PCL-PEO-R:
Learn from else's experience drying, heavily steam purified dimethylaminoethanol 30.6g, add new sodium reaction that 1.3g removes surface impurity and generate the dimethylaminoethanol sodium solution and put in the moisture eliminator sealing and preserve standby.
In the stainless steel autoclave of careful exsiccant configuration mechanical stirring and internal cooling coil pipe, add above-mentioned dimethylaminoethanol sodium solution 14g (wherein containing sodium 0.5g) down at about 0 ℃, oxyethane 456g (PEO designs molecular weight 3000), sealed reactor after the nitrogen purging displaced air, speed with 300rpm begins to stir, polymerization gradually heats up, feed water coolant, careful controlled chilling discharge makes the temperature in the reaction system remain on 80-85 ℃, reacting kettle inner pressure is up to 0.7MPa, stopped reaction when pressure is reduced to 0.04MPa behind about 3-4hr, cooling, open reactor after the release, in product, add less water (～5mL), acidic white earth, again be warmed up to about 110 ℃ and also under agitation vacuumize dehydration 30min, obtain the thick product 412g of Alpha-hydroxy-ω-dimethylamino Soxylat A 25-7 while hot behind the suction filtration.
The gained crude product is dissolved in makes into homogeneous solution in the tetrahydrofuran (THF), dropwise being added drop-wise to then in cold (5 ℃) anhydrous diethyl ethers of 10 times of amounts filters precipitation then, leach thing again through cold anhydrous diethyl ether washing, the suction filtration of 5 times of amounts, obtain purified Alpha-hydroxy-ω-dimethylamino polyoxyethylene ether product after the vacuum-drying.
2, PCL-PEO section synthetic among the PCL-PEO-R:
Get aforementioned Alpha-hydroxy-ω-dimethylamino Soxylat A 25-7 and reflux a few hours in dry benzene, normal pressure steams benzene to take away water, puts P
2O
5Preserve standby in the vacuum drier.6-caprolactone is through CaH
2Drying at least behind the 48hr with preceding decompression (62 ℃ ,～1mmHg) steam.
Difference according to the design molecular weight, in three tube sealings, add aforementioned careful exsiccant Alpha-hydroxy-ω-dimethylamino Soxylat A 25-7 3g, 1.5g, 1g respectively, add each one of 7g, 8.5g, 9g 6-caprolactone and stannous octoate then respectively, through vacuumize fill drying nitrogen at least 3 times after under vacuum tube sealing, be buried in 140 ℃ of sand-baths behind the polymerase 17 2hr, stop heating, furnace cooling.Gained PEO-PCL is dissolved in 20mL CHCl respectively after tube sealing takes out
3In, under agitation be added drop-wise to then in the Virahol that 200mL is chilled to-5 ℃ and precipitate, obtain faint yellowly to the white solid powder, to drain in the rearmounted vacuum drier of suction filtration and obtain the PEO-PCL block polymer, total molecular weight is about 10000,20000 and 30000 respectively.Each sample is only observed a simple spike on the GPC spectrogram, illustrate that what obtain is the blend of block polymer rather than PEO and PCL.The GPC spectrogram as shown in Figure 2.
3,2-methoxyl group-2-oxo-1,3,2-dioxaphospholane (MEP) synthetic:
2-methoxyl group-2-oxo-1,3, the 2-dioxaphospholane is synthetic by synthetic route as follows.Concrete synthetic method is:
On exsiccant 500mL four-necked bottle, assemble magnetic agitation, constant pressure funnel, thermometer and reflux condensing tube, add PCl
3138g (1mol), CH
2Cl
2150mL.Add ethylene glycol 62g (1mol) in constant pressure funnel, under room temperature ethylene glycol dropwise is added dropwise in the four-necked bottle, reaction is acutely carried out and is emitted with a large amount of HCl.The rate of addition of control ethylene glycol carries out reacting balance, is added dropwise to complete in 2～3hr, continues stirring reaction 2hr at room temperature then.Temperature reaction system gradually at first makes CH subsequently
2Cl
2Steam (42 ℃), the water white transparency overhead product when underpressure distillation is collected 70 ℃ then obtains CDP 80.7g, yield about 64%.
In 250mL single port flask, add the benzene that aforementioned CDP and 150g cross with sodium backflow drying, in solution, rouse O a bubble of a bubble
2To the reaction solution back stopped reaction that no longer increases weight, the first pressure reducing and steaming benzene that heats up, 122-124 ℃ cut is collected under the 1mmHg in underpressure distillation again, and obtaining the water white transparency liquid product is COP66.5g, yield about 73%.The sample infrared spectrum is identical with the standard spectrogram.
In the exsiccant four-necked bottle, add methyl alcohol 17g (0.53mol), anhydrous triethylamine 53.3g (0.53mol), anhydrous THF 320mL puts cryosel and is cooled to about-10 ℃ under stirring in bathing.Other gets the exsiccant constant pressure funnel, and dress COP 76g and anhydrous THF 40mL dropwise add in the reaction system, occur the triethylamine hydrochloride white precipitate immediately, and temperature also raises to some extent.The control rate of addition maintains below 5 ℃ reaction system, is added dropwise to complete in about 2.5hr.Dropwising the back continues to finish reaction after stirring reaction 1hr recession deicing salt bath makes reaction system be warmed up to room temperature continuation stirring reaction 2hr naturally.Suction filtration is removed the triethylamine hydrochloride precipitation, divide washing leaching cake three times with 250mLTHF, underpressure distillation removes the THF that desolvates in the rearmounted 50 ℃ of oil baths of merging mother liquor, continue then intensification oil bath to 60 ℃ with behind the oil pump underpressure distillation 2hr under reduced pressure cool to room temperature, light yellow transparent liquid residual in the matrass is MEP, meter 68.9g, yield about 94%.
4, block polymer PCL-PEO-R synthetic that has methyl Phosphorylcholine end group:
Each 1g of PCL-PEO that gets the different molecular weight of preparation in (2) respectively is dissolved among the 10mL THF, respectively adds the MEP of preparation among the 0.2g (3) again, finishes reaction in 40 stirring reactions, one week back.Reaction system is added drop-wise to respectively in the Virahol that 100mL is chilled to-5 ℃ precipitates, behind the suction filtration with cold diethyl ether repetitive scrubbing filter cake repeatedly the final vacuum drying obtain target product PCL-PEO-R.Product is dissolved in CDCl
3Middle mensuration
31P-NMR observes the peak of tangible phosphoric, illustrates that required methyl Phosphorylcholine end group is connected on the block polymer.
31The p-NMR spectrogram as shown in Figure 3.
5, PCL-PEO-R adds modified polyurethane material in the urethane to blending method:
To be that soft section thermoplastic polyurethane is dissolved in the solution for standby that is mixed with concentration 0.1g/mL among the DMF with polycaprolactone, the PCL-PEO-R that other gets aforementioned total molecular weight 30000 is dissolved in the solution that is mixed with concentration 0.3g/mL among the DMF, getting two kinds of solution 10mL and 1mL respectively mixes in small beaker, the rearmounted diameter 65mm of vacuum deaerator, the tetrafluoroethylene culture dish of dark 5mm vapors away solvent DMF in 40 ℃, obtains transparent film.Film is cut into the sequin of diameter 6mm, immerse after in the phosphate buffer soln of 0.1mol/L pH7.4, soaking a night
125In the fibrinogen solution of I isotopic enrichment, 1840 gamma calculating instruments with PE company are measured the protein molecule quantity of adsorbing on the sample, compare with the pure urethane sample that makes under the similarity condition that does not add PCL-PEO-R, blank sample adsorbed proteins quantity is 0.725g/cm
2, the sample adsorbed proteins quantity after the modification is 0.6g/cm
2, reduced by 17%.
By same quadrat method, the PCL-PEO-R of molecular weight 10000 is 5% o'clock at addition, and the protein adsorption quantity of sample is 0.492g/cm after the modification
2, reduced by 32%.
6, PCL-PEO-R adds modified polyvinyl chloride in the polyvinyl chloride to blending method:
Polyvinyl chloride is dissolved in the solution for standby that is mixed with concentration 0.17g/mL among the THF, the PCL-PEO-R that other gets aforementioned total molecular weight 20000 is dissolved in the solution that is mixed with concentration 0.2g/mL among the DMF, getting two kinds of solution 10mL and 1.5mL respectively mixes in small beaker, the rearmounted diameter 65mm of vacuum deaerator, the tetrafluoroethylene culture dish of dark 5mm vapors away solvent under room temperature, obtain semitransparent thin film.Film is cut into the sequin of diameter 6mm, immerse after in the phosphate buffer soln of 0.1mol/L pH7.4, soaking a night
125In the fibrinogen solution of I isotopic enrichment, 1840 gamma calculating instruments with PE company are measured the protein molecule quantity of adsorbing on the sample, compare with the pure polyvinyl chloride sample that makes under the similarity condition that does not add PCL-PEO-R, blank sample adsorbed proteins quantity is 0.675g/cm
2, the sample adsorbed proteins quantity after the modification is 0.301g/cm
2, reduced by 55%.
7, PCL-PEO-R adds modified pvc film in the polyvinyl chloride to surface preparation:
The block polymer PCL-PEO-R that will have methyl Phosphorylcholine end group is dissolved in the solution that is mixed with 1%-10% (wt/V) in the methanol/acetone mixed solvent (volume ratio 1: 2), get the sequin that the commodity polyvinyl chloride film cuts into diameter 6mm, drop into to soak in the above-mentioned solution to take out to put on the filter paper after one hour and dry, vacuum extracts solvent thermal treatment 1 hour in 85 ℃ baking oven after 1 hour then, measure absorption of proteins quantity with the measuring method in (5), the result shows, the quantity of the polyvinyl chloride adsorbed proteins after the modification obviously reduces the highest decreasing by more than 70%.
Claims (9)
1, a kind of polycaprolactone-polyethylene glycol block copolymer is characterized in that its structural formula is expressed as follows:
m＝10-1000；n＝10-100；x＝2-10；
R
1，R
2＝CH
3，CH
2CH
3
R
3＝CH
3，(CH
2)
yCH
3(y＝1-20)
The molecular weight of PCL section is 1000-100000, and the molecular weight of PEO section is 400-5000, and R is the alkyl phosphorylcholine with different structure.
2, polycaprolactone-polyethylene glycol block copolymer according to claim 1 is characterized in that the alkyl that atom of tertiary amine N and PEO spacer groups are made up of 2-4 carbon atom.
3, polycaprolactone-polyethylene glycol block copolymer according to claim 1, saturated or the undersaturated alkyl alcohol of the straight or branched that the alkyl alcohol that it is characterized in that constituting alkyl phosphorylcholine is made up of 1-20 carbon atom wherein can also have groups such as one or more hydroxyls, halogen Cl, Br, I as required.
4, the method for making of polycaprolactone-polyethylene glycol block copolymer as claimed in claim 1 is characterized in that this method for making may further comprise the steps:
(1) a synthetic terminal hydroxy group, the other end has the PEO of tertiary amine group;
(2) at the synthetic PCL segment of hydroxyl one end of PEO;
(3) utilize the chemical reaction of tertiary amine group to connect the alkyl phosphorylcholine group that needs.
5, the method for making of polycaprolactone-polyethylene glycol block copolymer according to claim 4, the method that it is characterized in that step (1) is that to select the alkyl alcohol that has tertiary amine group for use be initiator, the PEO of ring opening synthesis one terminal hydroxy group, an end tertiary amine groups under the negatively charged ion effect.
6, the method for making of polycaprolactone-polyethylene glycol block copolymer according to claim 5, it is characterized in that to contain alkyl alcohol and the sodium Metal 99.5 or the reaction of potassium hydroxide anionic initiator of tertiary amine and sloughing water through careful exsiccant earlier making corresponding alkoxide, add in the autoclave then, remove the airtight and oxyethane of input requirement once or several times behind oxygen and the water, react to oxyethane consumption at 60-120 ℃ and to finish, take out adding acid neutralization, obtain the PEO of a terminal hydroxy group, an end tertiary amine groups after making with extra care.
7, the method for making of polycaprolactone-polyethylene glycol block copolymer according to claim 4, the method that it is characterized in that step (2) is the PEO that step (1) prepares to be mixed with the careful dried 6-caprolactone of the warp of requirement add in the tube sealing, add a small amount of stannous octoate catalyst, fill N repeatedly
2, at vacuum lower seal tube sealing, tube sealing is put 140 ℃ of down reaction coolings after at least 72 hours, take out and be dissolved in the chloroform solvent, splash into then and precipitate in the cold isopropanol solvent, repeat said process and obtain the PCL-PEO block polymer after once.
8, the method for making of polycaprolactone-polyethylene glycol block copolymer according to claim 4, the method that it is characterized in that step (3) is with glycol and PCl
3Reaction obtains the chlorodioxin phosphorus heterocycle, obtain chlorination oxo dioxy phosphorus heterocycle through dioxygen oxidation, be reflected at the saturated or unsaturated alkyl that has or do not have hydroxyl or halogen is pure that dehydrochlorination obtains alkoxyl group oxygen phosphorus heterocycle alkane in the alkaline environment again, get thing and PCL-PEO 1 day time of reaction in the organic solvent of room temperature or slightly heating to 1 week, add precipitation agent and be settled out product, and remove unreacted alkoxyl group oxygen phosphorus heterocycle alkane through the solvent repetitive scrubbing, obtain the block polymer PCL-PEO-R product that target has the alkyl phosphorylcholine end group.
9, as claim 1, the application of 2 or 3 described polycaprolactone-polyethylene glycol block copolymers in the preparation bio-medical material.
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