CN106397727A - Triblock copolymer with high biocompatibility and preparation method and application thereof - Google Patents
Triblock copolymer with high biocompatibility and preparation method and application thereof Download PDFInfo
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- CN106397727A CN106397727A CN201610792708.4A CN201610792708A CN106397727A CN 106397727 A CN106397727 A CN 106397727A CN 201610792708 A CN201610792708 A CN 201610792708A CN 106397727 A CN106397727 A CN 106397727A
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Abstract
The invention discloses a triblock copolymer with high biocompatibility. A general formula of the triblock copolymer is A-b-B-b-C, wherein A, B and C are of block structures, B is a block chain extender, A represents a soft segment material with high hydrophily and is a block formed by at least one of polyethylene glycol, polypropylene glycol and polyether amine; B represents a rigid hard segment material with high hydrophobicity and is a block formed by at least one of polycarbonate and polymethyl methacrylate; C represents a flexible polymer and is a block formed by at least one of polydimethylsiloxane and poly(2-hydroxyethyl methacrylate). A permeable membrane prepared from the triblock copolymer has highly-controlled micromolecule permeability, good water resistance and heat resistance, and adjustable hydrophily and biocompatibility.
Description
Technical field
The present invention relates to block copolymer technical field and in particular to a kind of triblock copolymer of high-biocompatibility and
Its preparation method and application.
Background technology
Implantating biological sensors refer to a kind of can by some or all of implantation human body sensor device, it is permissible
In the content not needing added regent and measure target analyte molecule under conditions of being previously isolated from process body fluid or blood.Implantation
The advantage of formula biology sensor is can to measure some time dependent important physiology and pathological parameter in vivo with continuity, than
As blood oxygen, blood sugar, antiviral antibody etc., thus more directly the sign of reflection measurand is because of environmental change, physical exertion, diet
The change producing with medicine.Generally, the sensing part of implantable sensor needs to produce with in-house analyte
Certain interaction just can detect presence of analyte, and therefore, implantating biological sensors are controlled with the interaction of implanting tissue
Property represents main feature and the technical difficulty of implanted sensing technology.Due to inside of human body environment, especially microbiological ring
Border complex, the current mankind understand limited to the interaction between implantable sensor and implanting tissue.For example implantation passes
The surface mass of sensor and the otherness of human body component can cause the allosome rejection mechanism of human body, thus generating one layer mainly
The biological separation layer being made up of fibrin.Separation layer can cause sensor to completely cut off with implanting tissue, makes sensor and tissue fluid
Molecule infiltration and exchange hindered, sensor will lose accuracy to the detection of analyte concentration.Therefore how to reduce different
Thing rejection, the biocompatibility improving sensor is the key improving sensor accuracy and service life, and this is typically
To be realized by the film that the surface in sensor and contact tissue increases by a floor height biocompatibility.
Biocompatibility permeable membrane has a very high technical requirement to its composition, for example extremely low cytotoxicity, well
Hydrophily and biocompatibility, the diffusion performance suitable to target analytes and the barrier property to potential interference thing,
And in given use time hydrolysis, heat-resisting and resistance to other degradation mechanisms etc..Simultaneously because producing, transporting
Requirement with storage is in addition it is also necessary to this material has stable chemical molecular structure so as in long period before it is being used
Keep stable property.Therefore, the selection of current biocompatibility permeable membrane is very limited.At present, adopt such permeable membrane more
The high-biocompatibility polymer being commonly recognized with polyethylene glycol, poly- (2- hydroxyethyl methacrylate) etc. or its mixture system
Become, but majority be poor to the controllability of diffusion and water-fast poor heat resistance, can be affected by the surrounding environment generation change of properties,
Thus be unfavorable for producing and long-term storage.
Content of the invention
It is an object of the present invention to provide a kind of triblock copolymer of high-biocompatibility and its preparation method and application, to solve
Certainly the deficiencies in the prior art.
The present invention employs the following technical solutions：
A kind of triblock copolymer of high-biocompatibility, the formula of this triblock copolymer is A-b-B-b-C, wherein,
A, B, C are block structure, and b is block chain extender, and A represents the soft section material of high-hydrophilic, are polyethylene glycol, polypropylene glycol, gather
The block that at least one of ether amines are constituted；B represents the hard section material of rigid high hydrophobicity, is Merlon, polymethylacrylic acid
The block that at least one of methyl esters is constituted；C represents flexible polymer, is dimethyl silicone polymer, poly- (methacrylic acid -2- hydroxyl
Ethyl ester) at least one of constitute block.
Further, b is isocyanates chain extender, including methyl diphenylene diisocyanate, hexa-methylene two isocyanide
One or more of acid esters, dicyclohexyl methyl hydride diisocyanate.
Further, the number-average molecular weight of A block is in 200-10000；The number-average molecular weight of B block is in 1000-20000；C
The number-average molecular weight of block is in 1000-20000.
Further, the mass fraction of three class blocks and block chain extender is as follows：A block is 1-10 part, and B block is 1-5
Part, C block is 1-5 part, and the part by weight of block chain extender is 1-3 part.
Further, A-b, passes through urea between B-b, C-b or carbamate groups is covalently bonded.
The preparation method of the triblock copolymer of above-mentioned high-biocompatibility, comprises the steps：
Step one, by the soft section material of high-hydrophilic, the hard section material of rigid high hydrophobicity, flexible polymer, be added to
In organic solvent, mix at 30-45 DEG C；
Step 2, in the mixed solution of step one, add catalyst, and be added dropwise over block chain extender, be warming up to 55-
70 DEG C, react 12-20h；
Step 3, deionized water of adding in the reaction solution of step 2, reaction 12h-18h；
After step 4, cooling, product rinsed, filters, being dried, obtaining described triblock copolymer.
Further, the organic solvent of step one includes oxolane or isobutanol, and the volume of organic solvent and height are hydrophilic
Property soft section material, the hard section material of rigid high hydrophobicity, flexible polymer total mass ratio be 2-10ml:1g.
Further, the catalyst of step 2 includes triethylene diamine or dibutyl two isooctyl acid tin.
Further, the soft section material of the volume of the deionized water of step 3 and high-hydrophilic, rigid high hydrophobicity hard
Section material, flexible polymer total mass ratio are 1-10ml:1g.
The triblock copolymer of above-mentioned high-biocompatibility is preparing implantating biological sensors biocompatibility permeable membrane
In application.
Beneficial effects of the present invention：
1 present invention incorporates the advantage of single many dimeric molecules of three types that its block copolymer is had is adjustable
Permeability, the characteristic such as adjustable physical property and preferable hydrolytic stability and heat-resistant stability, simple with by many for three classes dimeric molecules
They can be prevented film forming by chain extending reaction combination using the isocyanates chain extender such as diisocyanates by single mixed phase ratio
During occur microfacies position segregation phenomenon.
2nd, after triblock copolymer film forming of the present invention, its physicochemical properties is more stable, than simple polyethers and polyesters
Polyurethane hydrolysis heat resistance is more preferable.
3rd, due to the presence of Equations of The Second Kind hard section block, the copolymer molecule after film forming is not susceptible to because of molecules align restructuring
The film surface change of properties causing, especially hydrophilic change.
4th, the hydrophily of this segmented copolymer, permeance property and physical strength can be by adjusting every kind of block in material
In percentage realize continuously adjust.
Brief description
Fig. 1 compares for anti-hydrolytic performance.
Fig. 2 compares for heat resistance.
Fig. 3 compares for film surface hydrophilic contact angle storage-stable.
Specific embodiment
With reference to embodiment and accompanying drawing, the present invention is done and further explain.The following example is merely to illustrate this
Bright, but be not used to limit the practical range of the present invention.
A kind of triblock copolymer of high-biocompatibility, the formula of this triblock copolymer is A-b-B-b-C, wherein,
A, B, C are block structure, and b is block chain extender, passes through urea or carbamate groups is covalently bonded between A-b, B-b, C-b.A
Represent the soft section material of high-hydrophilic, be the block that at least one of polyethylene glycol, polypropylene glycol, polyetheramine are constituted, such is embedding
Section has good water solubility, can allow target analyte molecule free permeation.B represents the hard section material of rigid high hydrophobicity,
The block constituting at least one of Merlon, polymethyl methacrylate, such block provides necessary physical strength
With the performance of heat-resisting hydrolysis, make the stability of permeable membrane more preferably.C represents flexible polymer, is dimethyl silicone polymer, gathers
The block that at least one of (2-hydroxyethyl methacry-late) is constituted, this kind of block serves before certain transitional function makes
Two class blocks are not susceptible to microphase-separated in mixing and film forming.The number-average molecular weight of A block is in 200-10000；The number of B block
Average molecular weight is in 1000-20000；The number-average molecular weight of C block is in 1000-20000.B represents block chain extender, is isocyanates
Class chain extender, including in methyl diphenylene diisocyanate, hexamethylene diisocyanate, dicyclohexyl methyl hydride diisocyanate
One or more.It is connected by chain extension mechanism by isocyanates chain extender between block and block, thus generating stable
Polyurethane or polyureas segmented copolymer.The mass fraction of three class blocks and block chain extender is as follows：A block is 1-10
Part, B block is 1-5 part, and C block is 1-5 part, and the part by weight of block chain extender is 1-3 part.
The preparation method of the triblock copolymer of above-mentioned high-biocompatibility, comprises the steps：
Step one, by the soft section material of high-hydrophilic, the hard section material of rigid high hydrophobicity, flexible polymer, be added to
In organic solvent, mix at 30-45 DEG C；Organic solvent includes oxolane or isobutanol, the volume of organic solvent and
The soft section material of high-hydrophilic, the hard section material of rigid high hydrophobicity, flexible polymer total mass ratio are 2-10ml:1g.
Step 2, in the mixed solution of step one, add catalyst, and be added dropwise over block chain extender, be warming up to 55-
70 DEG C, react 12-20h；Catalyst includes triethylene diamine or dibutyl two isooctyl acid tin.
Step 3, deionized water of adding in the reaction solution of step 2, reaction 12h-18h；The volume of deionized water and
The soft section material of high-hydrophilic, the hard section material of rigid high hydrophobicity, flexible polymer total mass ratio are 1-10ml:1g.
After step 4, cooling, product rinsed, filters, being dried, obtaining described triblock copolymer.
The triblock copolymer of above-mentioned high-biocompatibility is preparing implantating biological sensors biocompatibility permeable membrane
In application.The permeable membrane of preparation has highly controllable small molecule permeability, good water-fast heat resistance and adjustable parent
Aqueous and biocompatibility, this is mainly by realizing containing amphiphilic multiblock urea or polyurethane.
Embodiment 1
Raw material：Polyetheramine, number-average molecular weight 1000, quality is 25g；PCDL, number-average molecular weight 5000, matter
Measure as 10g；Diaminourea blocks dimethyl silicone polymer, number-average molecular weight 5000, and quality is 15g；Oxolane, 100ml；Hexichol
Dicyclohexylmethane diisocyanate, quality is 12g；Deionized water 50ml.
Step one, by polyetheramine, PCDL, diaminourea end-blocking dimethyl silicone polymer, be added to tetrahydrochysene furan
In muttering, mix at 40 DEG C.
Step 2, in the mixed solution of step one, add triethylene diamine, and be added dropwise over diphenyl methane two isocyanide
Acid esters, is warming up to 65 DEG C, reacts 12h.
Step 3, deionized water of adding in the reaction solution of step 2, reaction 12h.
After step 4, cooling, product rinsed, filters, being dried, obtaining described triblock copolymer.
Embodiment 2
Raw material：Polypropylene glycol, number-average molecular weight 2000, quality is 20g；PCDL, number is divided equally
Son amount 2000, quality is 15g；Polymethyl methacrylate, number-average molecular weight 2000, quality is 15g；Diaminourea blocks poly- diformazan
Radical siloxane, number-average molecular weight 8000, quality is 15g；Oxolane, 500ml；3g methyl diphenylene diisocyanate and 9g bis-
Diphenylmethane diisocyanate；Deionized water 500ml.
Step one, by polypropylene glycol, PCDL, polymethyl methacrylate, diaminourea end-blocking
Dimethyl silicone polymer, is added in oxolane, mixes at 30 DEG C.
Step 2, in the mixed solution of step one, add triethylene diamine, and be added dropwise over diphenyl methane two isocyanide
Acid esters and the mixed liquor of dicyclohexyl methyl hydride diisocyanate, are warming up to 55 DEG C, react 14h.
Step 3, deionized water of adding in the reaction solution of step 2, reaction 18h.
After step 4, cooling, product rinsed, filters, being dried, obtaining described triblock copolymer.
Embodiment 3
Raw material：Amino-terminated polypropylene glycol, molecular weight 500, quality 15g；Polyetheramine, molecular weight 600, quality 10g；Poly-
(bisphenol a carbonate), molecular weight is 5000, quality 25g；Diaminourea blocks dimethyl silicone polymer, and molecular weight is 20000, matter
Amount 10g；Poly- (2-hydroxyethyl methacry-late), molecular weight is 5000, quality 5g；Isobutanol 150ml；Hexa-methylene two isocyanide
Acid esters, quality 15g；Deionized water 150ml.
Step one, by amino-terminated polypropylene glycol, polyetheramine, poly- (bisphenol a carbonate), diaminourea end-blocking poly dimethyl silicon
Oxygen alkane, poly- (2-hydroxyethyl methacry-late), are added in isobutanol, mix at 35 DEG C.
Step 2, in the mixed solution of step one, add dibutyl two isooctyl acid tin, and be added dropwise over hexa-methylene two
Isocyanates, is warming up to 60 DEG C, reacts 16h.
Step 3, deionized water of adding in the reaction solution of step 2, reaction 14h.
After step 4, cooling, product rinsed, filters, being dried, obtaining described triblock copolymer.
Embodiment 4
Raw material：Polypropylene glycol, number-average molecular weight 10000, quality 30g；PCDL, the equal molecule of number
Amount 2000, quality 5g；Polymethyl methacrylate, number-average molecular weight 2000, quality 5g；Poly- (2-hydroxyethyl methacry-late),
Number-average molecular weight 20000, quality 15g；Isobutanol 600ml；Dicyclohexyl methyl hydride diisocyanate 20g；Deionized water 300ml.
Step one, by polypropylene glycol, PCDL, polymethyl methacrylate, poly- (metering system
Acid -2- hydroxyl ethyl ester), it is added in isobutanol, mix at 45 DEG C.
Step 2, in the mixed solution of step one, add dibutyl two isooctyl acid tin, and be added dropwise over dicyclohexyl first
Alkane diisocyanate, is warming up to 70 DEG C, reacts 20h.
Step 3, deionized water of adding in the reaction solution of step 2, reaction 16h.
After step 4, cooling, product rinsed, filters, being dried, obtaining described triblock copolymer.
Anti-hydrolytic performance compares
Polyester-polyurethane made by the triblock copolymer that prepare embodiment 1 and poly- (ethylene glycol adipate), ring
Polyether-polyurethane made by oxidative ethane-expoxy propane is prepared into film respectively, carries out anti-hydrolytic performance and compares.Film preparation
Journey is as follows：Measured and monitored the growth of standing timber material is dissolved in organic solvent such as oxolane, is then spin coated onto in glass sheet surface and is heated to 40 DEG C directly
All evaporate to solvent, make to be measured and monitored the growth of standing timber material in glass surface formation film.
Each sample film (each sample about 0.1g) is separately immersed in the 0.1M sodium chloride solution of 10mL, at room temperature
(25 DEG C) preservations, took out sample when 0,5,10,15,20,25 days, and deionized water is cleaned and is dried, is then dissolved in sample
Organic solvent such as oxolane, measures its molecular weight distribution using modes such as SECs (SEC) and calculates number and divide equally
Son amount.The number-average molecular weight calculating is obtained " mean molecule quantity/initial molecular weight " compared with the sample not soaked
Ratio, represented with the form of percentage.As shown in figure 1, its mean molecule quantity significantly reduces after polyester-based polyurethane soaks, table
Show that its molecule is partially decomposed, its hydrolytic resistance is poor.New material prepared by embodiment 1 and polyether polyurethane have preferably
Hydrolysis resistance.
Heat resistance compares
Polyester-polyurethane made by the triblock copolymer that prepare embodiment 1 and poly- (ethylene glycol adipate), ring
Polyether-polyurethane made by oxidative ethane-propylene oxide polyether is prepared into film respectively, carries out heat resistance and compares.Film preparation
Process is as follows：Measured and monitored the growth of standing timber material is dissolved in organic solvent such as oxolane, is then spin coated onto in glass sheet surface and is heated to 40 DEG C
Until solvent all evaporates, make to be measured and monitored the growth of standing timber material in glass surface formation film.
Each sample film (each sample about 0.1g) is placed in nature of glass culture dish, is placed in 60 DEG C of drying boxes and preserves,
Take out a sample after 0,5,10,15,20 weeks, deionized water is cleaned and is dried, and then sample is dissolved in organic solvent such as
Oxolane, is measured its molecular weight distribution and is calculated number-average molecular weight using modes such as SECs (SEC).To calculate
The number-average molecular weight drawing obtains the ratio of " mean molecule quantity/initial molecular weight " compared with the sample not soaked, and uses hundred
The form dividing ratio represents.
As shown in Fig. 2 its mean molecule quantity significantly reduces after polyether polyurethane soaks, represent its molecule because of the oxygen that is heated
Change and decomposed, its heat resistance is poor.New material prepared by embodiment 1 and polyester polyurethane have preferably heat-resisting point
Solution resistance.
Film surface hydrophilic contact angle storage-stable compares
New material is the triblock copolymer of embodiment 1 preparation and PEG+PDMS blend, PEG+PDMS copolymer are carried out
Film surface hydrophilic contact angle compares.Wherein PEG+PDMS blend is that (PEG contains only A class block polyethylene glycol
Polymer) and dimethyl silicone polymer (PDMS contains only B class or the polymer of C class block) mixing and the macromolecule made
Material, copolymer is double block macromolecular materials above two homopolymers being generated polyureas or polyurethane by polymerisation.
Hydrophilic contact angle experimental technique, by material of being measured and monitored the growth of standing timber is dissolved in organic solvent such as oxolane, is then spin coated onto in glass
Glass piece surface is simultaneously heated to 40 DEG C until solvent all evaporates, and makes to be measured and monitored the growth of standing timber material in glass surface formation film, then film
Sample preservation is in room temperature (about 25 DEG C) and indoor routine relative humidity (about 20%-40%).Periodically (such as every month) by sample
This taking-up, drips the deionized water of about 0.05-0.1mL thereon, and uses contact angle analysis-e/or determining water droplet and film
The angle that surface is formed, angle less explanation material surface hydrophily is higher.
As shown in figure 3, homopolymer blend thing and diblock copolymer are after placing a period of time, its surface hydrophilicity is
Reduce, and the surface hydrophilicity of prepared new material in embodiment 1 is more stable, preserve at room temperature and still will not for 6 months
There is very big change.
Claims (10)
1. a kind of triblock copolymer of high-biocompatibility is it is characterised in that the formula of this triblock copolymer is A-b-B-
B-C, wherein, A, B, C are block structure, and b is block chain extender, and A represents the soft section material of high-hydrophilic, are polyethylene glycol, gather
The block that at least one of propane diols, polyetheramine are constituted；B represents the hard section material of rigid high hydrophobicity, is Merlon, poly- first
The block that at least one of base methyl acrylate is constituted；C represents flexible polymer, is dimethyl silicone polymer, poly- (metering system
Acid -2- hydroxyl ethyl ester) at least one of constitute block.
2. the triblock copolymer of high-biocompatibility according to claim 1 is it is characterised in that b is isocyanates
Chain extender, including in methyl diphenylene diisocyanate, hexamethylene diisocyanate, dicyclohexyl methyl hydride diisocyanate
One or more.
3. the triblock copolymer of high-biocompatibility according to claim 1 is it is characterised in that the number of A block is divided equally
Son amount is in 200-10000；The number-average molecular weight of B block is in 1000-20000；The number-average molecular weight of C block is in 1000-20000.
4. the triblock copolymer of high-biocompatibility according to claim 1 is it is characterised in that three class blocks and block
The mass fraction of chain extender is as follows：A block is 1-10 part, and B block is 1-5 part, and C block is 1-5 part, the weight of block chain extender
Ratio is 1-3 part.
5. the triblock copolymer of high-biocompatibility according to claim 1 is it is characterised in that A-b, B-b, C-b it
Between by urea or carbamate groups covalently bonded.
6. the preparation method of the triblock copolymer of the high-biocompatibility described in claim 1-5 any claim, it is special
Levy and be, comprise the steps：
Step one, by the soft section material of high-hydrophilic, the hard section material of rigid high hydrophobicity, flexible polymer, be added to organic
In solvent, mix at 30-45 DEG C；
Step 2, in the mixed solution of step one, add catalyst, and be added dropwise over block chain extender, be warming up to 55-70 DEG C,
Reaction 12-20h；
Step 3, deionized water of adding in the reaction solution of step 2, reaction 12h-18h；
After step 4, cooling, product rinsed, filters, being dried, obtaining described triblock copolymer.
7. the preparation method of the triblock copolymer of high-biocompatibility according to claim 6 is it is characterised in that step
One organic solvent includes oxolane or isobutanol, and the soft section material of the volume of organic solvent and high-hydrophilic, rigidity are high to dredge
Aqueous hard section material, flexible polymer total mass ratio are 2-10ml:1g.
8. the preparation method of the triblock copolymer of high-biocompatibility according to claim 6 is it is characterised in that step
Two catalyst includes triethylene diamine or dibutyl two isooctyl acid tin.
9. the preparation method of the triblock copolymer of high-biocompatibility according to claim 6 is it is characterised in that step
The soft section material of the volume of three deionized water and high-hydrophilic, the hard section material of rigid high hydrophobicity, the flexible total matter of polymer
Amount ratio is 1-10ml:1g.
10. the triblock copolymer of the high-biocompatibility described in claim 1-5 any claim is preparing implanted life
Application in thing biosensor organism compatible permeation film.
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