CN109651586A - The polyurethane containing selenium and the preparation method and application thereof of stable, controllable nitric oxide releasing - Google Patents
The polyurethane containing selenium and the preparation method and application thereof of stable, controllable nitric oxide releasing Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/08—Processes
- C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
- C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
- C08G18/4269—Lactones
- C08G18/4277—Caprolactone and/or substituted caprolactone
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
- C08G18/44—Polycarbonates
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
- C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
- C08G18/6633—Compounds of group C08G18/42
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2375/00—Characterised by the use of polyureas or polyurethanes; Derivatives of such polymers
- C08J2375/04—Polyurethanes
- C08J2375/06—Polyurethanes from polyesters
Abstract
The present invention relates to a kind of stabilizations, the polyurethane containing selenium of controllable nitric oxide releasing and the preparation method and application thereof, belong to biomedical material technology.Solves the technical problem that existing NO generates unstable, the long-term catalytic stability difference of material catalytic site.Polyurethane containing selenium of the invention is to contain O-CH in strand2‑CH2‑Se‑Se‑CH2‑CH2The polyurethane of-O group.This contains selenium polyurethane and organic selenium catalytic site is introduced into main polymer chain, has both substantially increased the stability of catalytic site, realizes continual and steady, controllable NO release；It is also equipped with the excellent mechanical property of polyurethane, structure designability, machinability and biocompatibility, NO donor, which can be efficiently catalyzed, using its blend film prepared decomposes release NO, and release is continual and steady, controllable, the activation and adherency that blood platelet can be effectively reduced are suitable as chronic blood contact class material.
Description
Technical field
The invention belongs to biomedical material technologies, and in particular to a kind of stabilization, controllable nitric oxide (NO) release
Polyurethane containing selenium and the preparation method and application thereof.
Technical background
As a kind of biogenic signaling molecule, NO not only has vasodilatory effect, additionally it is possible to effectively inhibit blood platelet
Activation promotes vessel endothelialisation, inhibits the proliferation of smooth muscle cell, inhibition thrombosis reduces the generation of inflammatory reaction.Cause
This, NO therapy is widely used in the treatment of cardiovascular related diseases as a kind of emerging treatment method in recent years.As
Optimal anticoagulation surface, blood vessel endothelium can be with 0.5-4.0 × 10-10mol cm-2min-1Rate secretion release NO, because
This, for bionical blood vessel endothelium, many researchs, which are dedicated to exploitation, can stablize the polymer material of release NO for cardiovascular disease
The treatment of disease.
In the prior art, assign material NO release function method it is usual there are two types of: method one will contain-SNO functional group
NO donor be introduced into polymeric matrix by way of physical doping or covalent bonding, prepare NO releasable material (NO-
releasingmaterials).Currently used NO donor be mainly nucleopilic reagent nitrence alcohol (diazeniumdiolate) and
S-nitrosothiol (S-nitrosothiol, RSNO).However there are NO phenomenon of burst release for the type NO releasable material, while NO is supplied
Body stability is poor, and the finiteness of material load NO donor makes the material cannot achieve controllable NO release steady in a long-term.Method
Two, it introduces the catalysts into polymeric matrix or stromal surface, preparation NO generates material (NO-generating
Materials), such material can be catalyzed RSNOs and decompose generation NO.Due to certain density endogenous naturally occurring in blood
RSNOs, including nitrosoglutathione (S-nitrosoglutathione, GSNO), nitrosocysteine (S-
Nitrosocycsteine, CysNO), nitrosoalbumin (S-nitrosoalbumin, Alb-SNO), therefore, NO generate material
The most possible stabilization sustained release for realizing NO of material.
There are two main classes: transition metal ions (Cu for the common catalyst of material of NO generation at present2+、Fe2+Deng) and it is organic
Selenium.The compatibility of transition metal-type catalyst and polymeric matrix is poor, and the form for generalling use organic ligand complex compound introduces
Into polymeric matrix.Since the stability of ligand is poor, the leakage of transition metal ions will lead to, to influence the catalysis of material
Stability and biocompatibility cannot achieve the sustained release of NO.Organic selenium class (connection selenium compound) bionical gluathione of catalyst
Peptide peroxidase (GPx) has preferable biocompatibility.But research at present will mostly join selenium class compound with coating shape
Formula coats or is grafted to material surface, and since coating stability is poor, this kind of catalytic surface is also faced with falling off for catalytic site,
And then influence whether the catalytic stability of material.
Summary of the invention
The skill of unstable, the long-term catalytic stability difference of material catalytic site is generated it is an object of the invention to solve existing NO
Art problem provides a kind of stabilization, polyurethane containing selenium of controllable NO release and the preparation method and application thereof.
It is as follows that the present invention solves the technical solution that above-mentioned technical problem is taken.
The present invention provides the polyurethane containing selenium of a kind of stabilization, controllable nitric oxide releasing, and it is strand that this, which contains selenium polyurethane,
In contain O-CH2-CH2-Se-Se-CH2-CH2The polyurethane of-O group.
Preferably, the structural formula of the polyurethane containing selenium is as shown in formula II or formula III:
In formula II and formula III, n is the integer of 10-40.
The present invention also provides aforementioned stable, the preparation method of the polyurethane containing selenium of controllable nitric oxide releasing, including it is following
Step:
Step 1: polyalcohol and dry solvent are added into reactor, dehydration is added different under inert atmosphere protection
Cyanate, reaction, obtains base polyurethane prepolymer for use as；
Step 2: connection selenium glycol is added into base polyurethane prepolymer for use as, reaction obtains polyurethane containing selenium (PU-Se)；
The polyalcohol and isocyanates additive amount meet the hydroxyl of polyalcohol and the isocyanate groups of isocyanates
Molar ratio is 1:(:2-3), the additional amount of connection selenium glycol guarantees NCO fully reacting in reaction system.
Preferably, the polyalcohol is polycaprolactone polyol or polycarbonate polyol.
Preferably, the solvent is n,N-Dimethylformamide or dimethyl sulfoxide.
Preferably, the isocyanates is hexamethylene diisocyanate (HDI).
Preferably, in the step 1, reaction temperature is 60-80 DEG C, reaction time 2-3h.
Preferably, in the step 2, reaction temperature is 40-80 DEG C, reaction time 6-12h.
Preferably, in the step 1, catalyst is added while isocyanates is added.
Preferably, the preparation method of the selenium glycol, comprising the following steps:
Step 1: selenium simple substance and deionized water are added into reactor, under inert gas shielding, it is water-soluble that sodium borohydride is added
The molar ratio of liquid, selenium simple substance and sodium borohydride is less than 1:2, reacts 1.5-3h at -10 DEG C -10 DEG C, obtains the first intermediate；
Step 2: the selenium simple substance with the selenium simple substance equivalent in step 1 is added into the first intermediate, at 80 DEG C -100 DEG C
0.5-1h is reacted, the second intermediate is obtained；
Step 3: ethylene bromohyrin is added into the second intermediate, the molar ratio of whole selenium simple substance of ethylene bromohyrin and addition
Greater than 1:1,8-12h is reacted at 20 DEG C -50 DEG C, obtains connection selenium glycol.
The present invention also provides the preparation methods of the blend film containing the above-mentioned polyurethane containing selenium, comprising the following steps:
Step 1: polyurethane (PU) and polyurethane containing selenium (PU-Se) are mixed, in obtained mixture, polyurethane containing selenium
10wt%-100wt% is accounted for, mixture is dissolved in solvent, the blend solution of 5-20wt% is accounted for resulting mixture；
Step 2: room temperature solvent flashing, high annealing is obtained containing selenium by blend solution drop coating to clean sheet glass
Polyurethane comixing film.
Preferably, the solvent is hexafluoroisopropanol or n,N-Dimethylformamide.
Preferably, in the mixture, polyurethane containing selenium accounts for 10wt%-20wt%；Mixture accounts in the blend solution
10-20wt%.
Compared with prior art, beneficial effects of the present invention:
Organic selenium catalytic site is introduced polymerization owner by the polyurethane containing selenium of stabilization, controllable nitric oxide releasing of the invention
In chain, the stability of catalytic site had both been substantially increased, has realized continual and steady, controllable NO release；It is excellent to be also equipped with polyurethane
Different mechanical property, structure designability, machinability and biocompatibility, especially with polycaprolactone polyol as poly- ammonia
When the soft segment of ester, moreover it is possible to assign material certain biodegradability.
Blend film of the invention can efficiently be catalyzed NO donor and decompose release NO, and discharge continually and steadily, controllably, carefully
Cellular toxicity is low, can effectively reduce the activation and adherency of blood platelet, is suitable as chronic blood contact class material.
Detailed description of the invention
In Fig. 1, (a) is the chemical structural formula of the connection selenium glycol of the embodiment of the present invention 1, (b) is the connection of the embodiment of the present invention 1
The characterization result of the nucleus magnetic hydrogen spectrum of selenium glycol is (c) characterization result of the nuclear-magnetism carbon spectrum of the connection selenium glycol of the embodiment of the present invention 1,
It (d) is the characterization result of the nuclear-magnetism selenium spectrum of the connection selenium glycol of the embodiment of the present invention 1.
Fig. 2 is in embodiment 1, and connection selenium glycol small molecule characterizes the catalytic activity of GSNO.
Fig. 3 is the nucleus magnetic hydrogen spectrum characterization knot of the polyester polyurethane of the embodiment of the present invention 2 and the polyurethane containing selenium of embodiment 3
Fruit.
In Fig. 4, (a) and (b) is respectively XPS and EDS the characterization knot of the blend film surface Se content of the embodiment of the present invention 4
Fruit.
Fig. 5 is the catalytic activity experimental result of polyester polyurethane blend film containing selenium of the embodiment of the present invention 4.
Fig. 6 is the polyester polyurethane NO average rate of release experimental result of blend film containing selenium of the embodiment of the present invention 4.
Fig. 7 is the polyester polyurethane catalytic stability experimental result of blend film containing selenium of the embodiment of the present invention 4.
Fig. 8 is the polyester polyurethane platelet attachment experiment result of blend film containing selenium of the embodiment of the present invention 4.
Fig. 9 is the nucleus magnetic hydrogen spectrum table of the polycarbonate polyurethane of the embodiment of the present invention 5 and the polyurethane containing selenium of embodiment 6
Levy result.
Figure 10 is that the catalytic activity of polycarbonate polyurethane blend film containing selenium of the embodiment of the present invention 7 and NO are averagely released
Put rate experiments result.
Figure 11 is the polycarbonate polyurethane platelet attachment experiment result of blend film containing selenium of the embodiment of the present invention 7.
Specific embodiment
For a further understanding of the present invention, embodiment of the present invention is described in detail below, but it is to be understood that
These descriptions are only further explanation the features and advantages of the present invention, rather than limiting to the claimed invention.
The polyurethane containing selenium of stabilization, controllable nitric oxide releasing of the invention, it is to contain in strand that this, which contains selenium polyurethane,
O-CH2-CH2-Se-Se-CH2-CH2The polyurethane of-O group.
In above-mentioned technical proposal, preferably the structural formula of the polyurethane containing selenium is as shown in formula II or formula III:
In formula II and formula III, n is the integer of 10-40.
The preparation method of the polyurethane containing selenium of stabilization, controllable nitric oxide releasing of the invention, comprising the following steps:
Step 1: polyalcohol and dry solvent are added into reactor, and dehydration, inert gas (nitrogen or argon gas) protection
Under, isocyanates is added, 60-80 DEG C of reaction 2-3h obtains base polyurethane prepolymer for use as；
Step 2: connection selenium glycol is added dropwise into base polyurethane prepolymer for use as, and 40-80 DEG C of reaction 6-12h, obtained reaction solution warp
Precipitating, filtering, drying, obtain polyurethane containing selenium (PU-Se).
In above-mentioned technical proposal, polyalcohol, solvent and isocyanates are all to prepare base polyurethane prepolymer for use as in the prior art
Common raw material, the present invention is to the type of base polyurethane prepolymer for use as, type and prepares raw material and is not particularly limited, can be according to this field public affairs
Know common sense selection and preparation；Preferred polyol is polycaprolactone polyol or polycarbonate polyol；Solvent is N, N- dimethyl
Formamide or dimethyl sulfoxide；Isocyanates is hexamethylene diisocyanate (HDI).For guarantee the polyurethane containing selenium preparation,
In step 1, the additive amount of polyalcohol and isocyanates meets the hydroxyl of polyalcohol and the isocyanate groups of isocyanates
Molar ratio is 1:(:2-3), in step 2, the additional amount of connection selenium glycol guarantees NCO fully reacting in drop reaction system, preferably
Lucky fully reacting.
In above-mentioned technical proposal, step 1 can add catalyst while isocyanates is added, and catalyst is polyurethane
Custom catalysts in pre-polymerization production procedure, such as stannous octoate；The additive amount of catalyst is also polyurethane prepolymer system
Common dose during standby, the generally 0.1-0.2% of polyol quality.
In above-mentioned technical proposal, connection selenium glycol is the prior art, and structural formula is as shown in formula I:
The present invention provides a kind of preparation method of selenium glycol, but not limited to this, comprising the following steps:
Step 1: selenium simple substance and deionized water are added into reactor, under inert gas (nitrogen or argon gas) protection, it is added
The molar ratio of sodium borohydride aqueous solution, selenium simple substance and sodium borohydride be less than 1:2 (i.e. selenium simple substance and sodium borohydride in molar ratio 1:
2 reactions, sodium borohydride can be excessive, preferably 1:(2-2.05)), 1.5-3h is reacted at -10 DEG C -10 DEG C, obtains the first intermediate；
Step 2: the selenium simple substance with the selenium simple substance equivalent in step 1 is added into the first intermediate, at 80 DEG C -100 DEG C
0.5-1h is reacted, the second intermediate is obtained；
Step 3: ethylene bromohyrin is added into the second intermediate, the molar ratio of whole selenium simple substance of ethylene bromohyrin and addition
Greater than 1:1, preferably 1:1.05,8-12h is reacted at 20 DEG C -50 DEG C, through filtering, extraction, separation, obtains connection selenium glycol.
The preparation method of blend film of the invention, comprising the following steps:
Step 1: polyurethane and polyurethane containing selenium are mixed, in obtained mixture, polyurethane containing selenium accounts for 8wt%-
Mixture is dissolved in solvent by 100wt%, and the blend solution of 5-20wt% is accounted for resulting mixture；
Step 2: room temperature solvent flashing, high annealing is obtained containing selenium by blend solution drop coating to clean sheet glass
Polyurethane comixing film.
In above-mentioned technical proposal, solvent is not particularly limited, and can play the role of dissolution, such as hexafluoroisopropanol or N,
Dinethylformamide；Course of dissolution can select normal-temperature dissolution still to dissolve by heating according to the actual situation, in general, hexafluoroisopropanol
It is dissolved at 20-30 DEG C, n,N-Dimethylformamide is at 50-80 DEG C, and general dissolution is by stirring to being completely dissolved.
In above-mentioned technical proposal, in mixture, the content of the polyurethane containing selenium is too low, can not play catalytic effect, content mistake
Height reduces mechanical property, therefore preferably accounts for 10wt%-20wt%.
In above-mentioned technical proposal, blend solution excessive concentration influences thin film mechanical performance, and concentration is too low, film formation time mistake
Journey, therefore mixture preferably accounts for 10-20wt%.
In above-mentioned technical proposal, polyurethane is common polymer in the prior art, and commercially available or laboratory system can be used
Standby, the present invention provides a kind of preparation method of polyurethane, but not limited to this.Polyurethane is prepared by the following method: first Xiang Fanying
Polycaprolactone polyol is added in device, is dehydrated, under inert gas protection, hexamethylene diisocyanate is added and catalyst is pungent
Sour stannous, reaction, obtains base polyurethane prepolymer for use as；Then addition and dry N,N-dimethylformamide into base polyurethane prepolymer for use as
Base polyurethane prepolymer for use as is diluted, 1,4-butanediol is then added, reacts, obtains polyurethane.Polyurethane and the poly- ammonia containing selenium of the invention
Polyurethane in ester may be the same or different, there is no limit.
The present invention is further illustrated with attached drawing with reference to embodiments.
Embodiment 1
Join the preparation of selenium glycol:
Step 1: selenium simple substance (3.0g) is suspended in 25ml deionized water, dripped under the conditions of nitrogen protection and ice-water bath
Add the deionized water solution (25ml) of sodium borohydride (3.0g), stirring to solution, which becomes, clarifies, and obtains the solution of the first intermediate.
Step 2: selenium simple substance (3.0g) is added in above-mentioned first midbody solution, stirred at 90 DEG C, react 0.5h,
Obtain the second midbody solution.
Step 3: continuing the aqueous solution (25ml) of 10.0g ethylene bromohyrin being added drop-wise to above-mentioned second midbody solution dropwise
In, it is stirred overnight at 40 DEG C, after filtering, mother liquor is extracted with ethyl acetate, collects organic phase, be spin-dried for the solvent, (leaching of silica gel post separation
Washing lotion: ethyl acetate/petroleum ether, v/v, 2:1), solvent is rotated, crocus solid is obtained, as connection selenium glycol.
The connection selenium glycol of embodiment 1 is detected.
1.1 magnetic resonance detection
As a result as shown in Figure 1.Using deuterated chloroform as deuterated reagent, nucleus magnetic hydrogen spectrum (400MHz,1H) data: δ (ppm):
3.93(m,4H),3.11(m,4H),2.13(s,2H).Nuclear-magnetism carbon spectrum (100MHz,13C) data: δ (ppm): 61.82,32.68.
Nuclear-magnetism selenium spectrum (400MHz,77Se) data: δ (ppm): 246.49 (s, 2Se).Prove the connection selenium two for being prepared for 1 structure of formula really
Alcohol.
1.2 catalytic activity are tested
Test philosophy: connection two alcohol catalysis GSNO of selenium discharges NO, and the NO of generation is unstable, and meeting air and water can be quickly oxidized
For nitrite ion, nitrite ion micro in solution can detecte by Griess reagent, and according to nitrite anions
The standard working curve of ion calculates the mole that catalysis generates NO, and the amount that NO is generated in the unit time is more, catalytic activity
It is higher.
Test process: first 3.2mg GSNO, 3.1mg GSH and 7.4mgEDTA are dissolved in 200ml PBS and being made into containing 50
The NO donor stock solution of μM GSNO, 50 μM of GSH and 100 μM of EDTA；Then 0.5mg, 1mg, 2mg and 5mg is taken to join selenium respectively
Glycol is dissolved in the solution for being made into that concentration is 0.2mM, 0.4mM, 0.8mM and 2mM in 10ml NO donor stock solution respectively, point
It does not take above-mentioned solution in 24 orifice plates, and is immediately placed in 37 DEG C of baking ovens, be protected from light, 4 multiple holes are arranged in every group of concentration；Then
50 μ L reaction solutions are taken out when reacting 2min, 20min and 40min respectively, and sequentially add each 50 μ L of Griess reagent A, B liquid,
Continue after being incubated for 10min at 37 DEG C, with light absorption value of the microplate reader detection mixed solution at 540nm.Finally according to nitrous acid
Radical ion standard working curve calculates the concentration for generating NO, as a result as shown in Figure 4.
Test result: as can be seen from Figure 4, connection selenium glycol small molecule has excellent catalytic activity, can quickly be catalyzed
GSNO discharges NO.
Embodiment 2
The preparation of polyester polyurethane:
Step 1: polycaprolactone polyol (16g, 2000 dalton of molecular weight) is dissolved in the dry DMF of 200ml,
It is heated to 70 DEG C；Under nitrogen protection, it is added dropwise 4.0g hexamethylene diisocyanate and 0.02g stannous octoate, 70 DEG C
Lower stirring 3h, obtains the first intermediate.
Step 2: the dry DMF solution of the 10ml containing 1.44g 1,4-butanediol is added dropwise into the first intermediate, it has been added
Bi Hou stirs 12h at 70 DEG C；Then reaction solution is deposited in 1L ether, washed with ether 2-3 times, collects crocus precipitating, very
Sky is dry to constant weight, obtains polyurethane PEU.
Embodiment 3
The preparation of polyester-type polyurethane containing selenium:
Step 1: polycaprolactone polyol (16g, 2000 dalton of molecular weight) is dissolved in the dry DMF of 200ml,
It is heated to 70 DEG C；Under nitrogen protection, it is added dropwise 4.0g hexamethylene diisocyanate and 0.02g stannous octoate, 70 DEG C
Lower stirring 3h, obtains the first intermediate.
Step 2: the dry DMF solution of 10ml that 4.0g connection selenium glycol is added dropwise is added into the first intermediate, addition is finished
Afterwards, 12h is stirred at 70 DEG C；Then reaction solution is deposited in 1L ether, washed with ether 2-3 times, collects crocus precipitating, vacuum
Drying obtains the PEU-Se of polyurethane containing selenium to constant weight.
The polyurethane containing selenium that the polyurethane and embodiment 3 prepare to embodiment 2 obtains has carried out the detection of nucleus magnetic hydrogen spectrum, ties
Fruit is as shown in Figure 2.PEU nucleus magnetic hydrogen spectrum (400MHz,1H) data: 3.98ppm (- CH2O-), 2.96ppm (- NHCH2),
2.27ppm(-CH2COO-), 1.54-1.27ppm (- CH2-CH2-CH2-).PEU-Se nucleus magnetic hydrogen spectrum (400MHz,1H) data:
4.18ppm(-NH-COO-CH2-CH2- Se-), 3.98ppm (- CH2O-), 3.11ppm (- NH-COO-CH2-CH2- Se-),
2.96ppm(-NHCH2), 2.27ppm (- CH2COO-), 1.54-1.27ppm (- CH2-CH2-CH2-).Nuclear-magnetism result demonstrates formula
The successful synthesis of 2 structure polyurethane containing selenium.
Embodiment 4
The preparation of the polyester-type film of polyurethane comixing containing selenium:
Step 1: by PEU and PEU-Se difference in mass ratio 100/0,99.5/0.5,98/2,95/5,90/10,80/20
With 50/50 mixing, it is dissolved in hexafluoroisopropanol, is made into the solution of 10wt% respectively, stirred at room temperature to being completely dissolved, obtained
Blend solution；
Step 2: by blend solution drop coating to clean sheet glass, it is poly- containing selenium to obtain polyester-type by room temperature solvent flashing 2h
Urethane blend film, anneal 1h at 120 DEG C, is respectively labeled as PEU, PEU-Se-0.5, PEU-Se-2, PEU-Se-5, PEU-
Se-10 and PEU-Se-20.
The performance of blend film prepared by embodiment 4 is detected.
The test of 4.1 surface Se contents
XPS and EDS detection PEU, PEU-Se-2, PEU-Se-5, PEU-Se-10, PEU-Se-20 and PEU- is respectively adopted
The content of Se-50 blend film surface selenium element, as a result as shown in Figure 4.Know the matter by adjusting PEU-Se in blend film
Score is measured, film surface Se content can be effectively regulated and controled.
The test of 4.2 catalytic activity
PEU, PEU-Se-0.5, PEU-Se-2, PEU-Se-10 and PEU-Se-20 are taken off from substrate of glass, are soaked respectively
Not in 2mL NO stock solution, 2h is reacted at 37 DEG C, 50 μ L solution is taken out every 20min, is separately added into Griess reagent A, B
Each 50 μ L, and light absorption value at 540nm is detected with microplate reader, it draws NO release profiles and simultaneously calculates NO average rate of release.As a result divide
Not not as shown in Figure 5 and Figure 6.
As can be seen from the results, compared with conventional polyurethanes, blend film containing selenium has excellent catalytic activity, when PEU-Se is low
When 2%, catalytic rate increases with the promotion of PU-Se content, and the determinant being catalyzed at this time is the concentration of catalyst；When
When PU-Se content is higher than 2wt%, film catalyst rate tends towards stability level, illustrates that catalyst concn has reached saturation value, at this time
The determinant of catalysis is changed into substrate toward film-solution interface migration rate from catalyst concn.
The test of 4.3 catalytic stabilities
By PEU-PDA-Se, PEU-Se-0.5, PEU-Se-2, PEU-Se-5, PEU-Se-10 and PEU-Se-20 each four
It takes off, is immersed in the PBS solution containing 50 μM of GSH respectively from substrate of glass, respectively the 0th day, the 1st day, the 3rd day,
Film is taken out at 8 days, the 16th day and the 30th day, and detects film catalyst performance with Griess reagent, as a result as shown in Figure 7.
As can be seen from the results: traditional coating PEU-PDA-Se catalytic stability of dopamine containing selenium is poor, and 1 is impregnated in PBS
After it, catalytic rate reduces 90% or more.Although and blend film containing selenium, in preceding 16 days soaking processes, catalytic rate has
Certain decline, but after 16 days, catalytic rate is basicly stable.And PEU-Se content is when reaching 10wt%, catalytic process certainly
Trot is changed into the control of substrate diffusion rate by catalyst concn control suddenly.Therefore blend film of the invention, which can have, realizes NO's
Stably and controllable release.PEU-Se-10 is the blend film containing selenium optimized, has best catalytic stability, is being impregnated 16 days
Later, catalytic rate no longer reduces, and can maintain the 61.22% of initial catalyst rate.
4.4 platelet attachment experiment
Test process: first extracting new fresh rabbit blood 2ml, and 15min is centrifuged under 1000rpm revolving speed, and it is rich to obtain upper layer blood platelet
Collect blood plasma (PRP)；Then blend film PEU, PEU-Se-5, PEU-Se-10 and PEU-Se-20 each 4 are immersed in PBS simultaneously
It is placed at 37 DEG C and balances 3h；Then after film taking-up being dried, surface adds 30 μ L to contain 50 μM of GSNO, 50 μM GSH and 100 μM
The PRP of EDTA, and 1h is incubated at 37 DEG C；It uses PBS repeated flushing film 5 times again, washes off nonadherent blood platelet,
6h is fixed in 2.5% (wt/v) glutaraldehyde solution；Volume fraction 10%, 30%, 50%, 70%, 90% and nothing are finally used respectively
Water-ethanol carries out serial dehydration to the blood platelet being adhered on film, after drying, observes blood platelet under a scanning electron microscope
Adhere to quantity and platelet PLA2.As a result as shown in Figure 8.
Test result: as shown in Figure 8, blend film containing selenium can reduce the activation and adherency of blood platelet, and PEU-Se contains
Amount is higher, is more obvious to the inhibiting effect of blood platelet.
Embodiment 5
The preparation of polycarbonate polyurethane:
Step 1: polycaprolactone polyol (16g, 2000 dalton of molecular weight) is dissolved in the dry DMF of 200ml,
70 DEG C are heated to, under inert gas protection, 4.0g hexamethylene diisocyanate and 0.02g stannous octoate is added dropwise,
3h is stirred at 70 DEG C.Obtain the first intermediate.
Step 2: the dry DMF solution of the 10ml that 1.44g 1,4-butanediol is added and be added dropwise into the first intermediate, adds
After entering, 12h is stirred at 70 DEG C, then reaction solution is deposited in 1L ether, washed with ether 2-3 times, and it is heavy to collect crocus
It forms sediment, is dried under vacuum to constant weight, obtains polyurethane PCU.
Embodiment 6
The preparation of polycarbonate type polyurethane containing selenium:
Step 1: polycarbonate polyol (10g, 2000 dalton of molecular weight) is dissolved in the dry DMF of 150ml,
70 DEG C are heated to, under inert gas protection, 2.52g hexamethylene diisocyanate and 0.02g stannous octoate is added dropwise,
3h is stirred at 70 DEG C.Obtain the first intermediate.
Step 2: the dry DMF solution of 10ml that 4.0g connection selenium glycol is added dropwise is added into the first intermediate, addition is finished
Afterwards, 12h is stirred at 70 DEG C, then reaction solution is deposited in 1L ether, washed with ether 2-3 times, collect crocus precipitating, vacuum
Drying obtains the PCU-Se of polyurethane containing selenium to constant weight.
The polyurethane containing selenium that the polyurethane and embodiment 6 prepare to embodiment 5 obtains has carried out the detection of nucleus magnetic hydrogen spectrum, ties
Fruit is as shown in Figure 9.PCU nucleus magnetic hydrogen spectrum (400MHz,1H) data: 4.10ppm (- CH2O COO-CH2), 3.59ppm (- CH2-
CH2-CH2-OCO-NH-),2.93ppm(-OCONHCH2), 2.30ppm (- CH2-CH2- OCOO-), 1.52ppm (- CH2-CH2-
CH2-OCO-NH-),1.35ppm(-CH2-CH2-CH2-NH-OCO-),1.21ppm(-CH2-CH2-CH2-NH-OCO-)。PCU-Se
Nucleus magnetic hydrogen spectrum (400MHz,1H) data: 4.17ppm (NH-COO-CH2-CH2- Se-), 4.10ppm (- CH2OCOO-CH2),
3.59ppm(-CH2-CH2-CH2-OCO-NH-),3.12ppm(-NH-COO-CH2-CH2- Se-), 2.93ppm (- OCONHCH2),
2.30ppm(-CH2-CH2- OCOO-), 1.52ppm (- CH2-CH2-CH2-OCO-NH-),1.35ppm(-CH2-CH2-CH2-NH-
OCO-),1.21p pm(-CH2-CH2-CH2-NH-OCO-).Nuclear-magnetism result demonstrates the successful conjunction of 3 structure polyurethane containing selenium of formula
At.
Embodiment 7
The polycarbonate type film preparation of thin polyurethane containing selenium:
Step 1: PCU and PCU-Se in mass ratio 100/0 and 90/10 mixing respectively is dissolved in N, N- dimethyl formyl
In amine, it is made into the solution of 10wt%, is heated to being completely dissolved at 80 DEG C, obtains blend solution.
Step 2: by blend solution drop coating to clean sheet glass, 50 DEG C of solvent flashings, anneal at 120 DEG C 1h, obtains
The film of polyurethane comixing containing selenium, is respectively labeled as PCU and PCU-Se-10.
The performance of blend film prepared by embodiment 7 is detected.
The test of 7.1 catalytic activity
PCU and PCU-Se-10 are taken off from substrate of glass, are immersed in 2mLNO stock solution respectively, is reacted at 37 DEG C
200min takes out 50 μ L solution every 20min, is separately added into each 50 μ L of Griess reagent A, B, and detect 540nm with microplate reader
Locate light absorption value, draw NO release profiles and calculates NO average rate of release.As a result respectively as shown in (a) and (b) in Figure 10.
As can be seen from the results, compared with PCU, PCU-Se-10 still shows excellent catalytic activity, illustrates that selenium two will be joined
Alcohol is introduced into polyurethane backbone as chain extender, can this result of stably catalyzed release NO have universality.
7.2 blend film platelet attachment experiments
Test method: first extracting new fresh rabbit blood 2ml, and 15min is centrifuged under 1000rpm revolving speed, and it is rich to obtain upper layer blood platelet
Collect blood plasma (PRP)；Then blend film PCU and PCU-Se-10 each 4 are immersed in PBS to be placed at 37 DEG C and balance 3h；So
After film taking-up is dried afterwards, the PRP that surface adds 30 μ L to contain 50 μM of GSNO, 50 μM of GSH and 100 μM of EDTA, and at 37 DEG C
Lower incubation 1h；It uses PBS repeated flushing film 5 times again, nonadherent blood platelet is washed off, in 2.5% (wt/v) glutaraldehyde solution
Middle fixed 6h；Finally respectively with volume fraction 10%, 30%, 50%, 70%, 90% and dehydrated alcohol to being adhered on film
Blood platelet carries out serial dehydration, after drying, observes platelet adhesion reaction quantity and platelet PLA2 under a scanning electron microscope.Knot
Fruit is as shown in figure 11.
Test result: as shown in Figure 11, blend film containing selenium can reduce the activation and adherency of blood platelet, with PU/PU-Se
Blend film result is consistent, illustrates that polyurethane containing selenium can effectively reduce platelet adhesion reaction with this result of activation with pervasive
Property.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (10)
1. stablizing, the polyurethane containing selenium of controllable nitric oxide releasing, which is characterized in that it is to contain in strand that this, which contains selenium polyurethane,
O-CH2-CH2-Se-Se-CH2-CH2The polyurethane of-O group.
2. the polyurethane containing selenium of stabilization according to claim 1, controllable nitric oxide releasing, which is characterized in that poly- containing selenium
The structural formula of urethane is as shown in formula II or formula III:
In formula II and formula III, n is the integer of 10-40.
3. the preparation method of the polyurethane containing selenium of stabilization of any of claims 1 or 2, controllable nitric oxide releasing, feature exist
In, comprising the following steps:
Step 1: polyalcohol and dry solvent are added into reactor, isocyanic acid is added under inert atmosphere protection in dehydration
Ester, reaction, obtains base polyurethane prepolymer for use as；
Step 2: connection selenium glycol is added into base polyurethane prepolymer for use as, reaction obtains polyurethane containing selenium；
The polyalcohol and isocyanates additive amount, meet mole of the hydroxyl of polyalcohol and the isocyanate groups of isocyanates
Than for 1:(:2-3), the additional amount for joining selenium glycol guarantees NCO fully reacting in reaction system.
4. the preparation method of the polyurethane containing selenium of stabilization according to claim 3, controllable nitric oxide releasing, feature exist
In the polyalcohol is polycaprolactone polyol or polycarbonate polyol；The isocyanates is hexa-methylene diisocyanate
Ester；The solvent is N,N-dimethylformamide or dimethyl sulfoxide.
5. the preparation method of the polyurethane containing selenium of stabilization according to claim 3, controllable nitric oxide releasing, feature exist
In in the step 1, reaction temperature is 60-80 DEG C, reaction time 2-3h；In the step 2, reaction temperature 40-80
DEG C, reaction time 6-12h.
6. the preparation method of the polyurethane containing selenium of stabilization according to claim 3, controllable nitric oxide releasing, feature exist
In, in the step 1, be added isocyanates while be additionally added catalyst.
7. the preparation method of the polyurethane containing selenium of stabilization according to claim 3, controllable nitric oxide releasing, feature exist
In the preparation method of the selenium glycol, comprising the following steps:
Step 1: selenium simple substance and deionized water are added into reactor, under inert gas shielding, sodium borohydride aqueous solution is added,
The molar ratio of selenium simple substance and sodium borohydride is less than 1:2, reacts 1.5-3h at -10 DEG C -10 DEG C, obtains the first intermediate；
Step 2: the selenium simple substance with the selenium simple substance equivalent in step 1 is added into the first intermediate, reacted at 80 DEG C -100 DEG C
0.5-1h obtains the second intermediate；
Step 3: ethylene bromohyrin is added into the second intermediate, the molar ratio of whole selenium simple substance of ethylene bromohyrin and addition is greater than
1:1 reacts 8-12h at 20 DEG C -50 DEG C, obtains connection selenium glycol.
8. the preparation containing stabilization of any of claims 1 or 2, the blend film of the polyurethane containing selenium of controllable nitric oxide releasing
Method, which comprises the following steps:
Step 1: polyurethane and polyurethane containing selenium are mixed, in obtained mixture, polyurethane containing selenium accounts for 8wt%-100wt%,
Mixture is dissolved in solvent, the blend solution of 5-20wt% is accounted for resulting mixture；
Step 2: room temperature solvent flashing, high annealing obtains the poly- ammonia containing selenium by blend solution drop coating to clean sheet glass
Ester blend film.
9. the preparation method of blend film according to claim 8, which is characterized in that the solvent be hexafluoroisopropanol or
N,N-dimethylformamide.
10. the preparation method of blend film according to claim 8, which is characterized in that in the mixture, the poly- ammonia containing selenium
Ester accounts for 10wt%-20wt%；Mixture accounts for 10-20wt% in the blend solution.
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