CN109929124A - It can be used for the body temperature stimulation shape memory gel and its preparation method and application of hemangioma embolism - Google Patents
It can be used for the body temperature stimulation shape memory gel and its preparation method and application of hemangioma embolism Download PDFInfo
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- embolism
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- hemangioma
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- 208000005189 Embolism Diseases 0.000 title claims abstract description 28
- 230000036760 body temperature Effects 0.000 title claims abstract description 26
- 201000011066 hemangioma Diseases 0.000 title claims abstract description 21
- 230000000638 stimulation Effects 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000000017 hydrogel Substances 0.000 claims abstract description 42
- 239000000499 gel Substances 0.000 claims abstract description 40
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims abstract description 32
- 239000008363 phosphate buffer Substances 0.000 claims abstract description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims abstract description 23
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 13
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims abstract description 12
- 229910001626 barium chloride Inorganic materials 0.000 claims abstract description 12
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Chemical compound CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 claims abstract description 11
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims abstract description 9
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims abstract description 9
- 238000011161 development Methods 0.000 claims abstract description 6
- 150000003254 radicals Chemical class 0.000 claims abstract description 5
- 239000003999 initiator Substances 0.000 claims description 46
- 239000003431 cross linking reagent Substances 0.000 claims description 33
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 27
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 27
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 230000000977 initiatory effect Effects 0.000 claims description 16
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 238000006116 polymerization reaction Methods 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000007654 immersion Methods 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 5
- 238000007334 copolymerization reaction Methods 0.000 claims description 5
- 235000019394 potassium persulphate Nutrition 0.000 claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000010526 radical polymerization reaction Methods 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 3
- -1 alkene nitrile Chemical class 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- 239000001307 helium Substances 0.000 claims description 3
- 229910052734 helium Inorganic materials 0.000 claims description 3
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 229920002521 macromolecule Polymers 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000008055 phosphate buffer solution Substances 0.000 claims description 3
- 230000001681 protective effect Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- 230000001737 promoting effect Effects 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- 238000000465 moulding Methods 0.000 claims 1
- 150000004968 peroxymonosulfuric acids Chemical class 0.000 claims 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims 1
- 229910052939 potassium sulfate Inorganic materials 0.000 claims 1
- 235000011151 potassium sulphates Nutrition 0.000 claims 1
- 238000011049 filling Methods 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 5
- 230000003446 memory effect Effects 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 230000008021 deposition Effects 0.000 abstract description 2
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- 239000011159 matrix material Substances 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical compound FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 6
- 229910000754 Wrought iron Inorganic materials 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 230000006399 behavior Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000002791 soaking Methods 0.000 description 4
- 229940030225 antihemorrhagics Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000006392 deoxygenation reaction Methods 0.000 description 3
- 230000010102 embolization Effects 0.000 description 3
- 230000000025 haemostatic effect Effects 0.000 description 3
- 244000309715 mini pig Species 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- VAZSKTXWXKYQJF-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)OOS([O-])=O VAZSKTXWXKYQJF-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000005202 decontamination Methods 0.000 description 1
- 230000003588 decontaminative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920002239 polyacrylonitrile Polymers 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 230000009329 sexual behaviour Effects 0.000 description 1
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Landscapes
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention, which provides, can be used for body temperature stimulation shape memory gel of hemangioma embolism and its preparation method and application, cause acrylonitrile by free radical, acrylamide and the polyethylene glycol dimethacrylate cross-linked polymeric in dimethyl sulfoxide, the organogel that will be obtained, it is immersed in 25 DEG C of phosphate buffers, and barium chloride solution, aqueous sodium persulfate solution are impregnated respectively, barium sulfate is deposited in gel network, PBS is then impregnated again and removes impurity, obtains the body temperature stimulation shape memory gel spring ring that can be used for hemangioma embolism.Preparation method is simple, prepares the embolism spring ring of water-setting matrix for the first time, improves the defect of the low Yi Chongtong of commercial metal spring ring filling rate；Body temperature is the stimulus of shape memory effect, and biology is friendly；Modulus under hydrogel room temperature is high, can directly be pushed；In-situ deposition barium sulfate make gel can X-ray development, and possess shape memory effect.
Description
Technical field
The present invention relates to shape memory gel technical fields, can be used for hemangioma embolism more specifically to one kind
, can the high-modulus of X-ray development, high-intensitive body temperature stimulation shape memory gel spring ring and preparation method thereof pass through it is dynamic to pig
Arteries and veins carries out embolism and shows that the hydrogel spring ring has good embolization effect.
Background technique
High recanalization rate is through one of serious problems urgently to be resolved in transcatheter arterial tumor Embolization aneurysm, this is quotient
The result of low filling rate caused by the high rigidity of metal elastic spring coil.The shape memory gel spring ring of Thermo-sensitive can be 20
DEG C PBS in be fixed as hard vertical bar form, and be transported in artery under the cooling of 20 DEG C of physiological saline by conduit,
Soften rapidly after encountering warm blood and is changed into spring shape.Target arterial is reached conveying a plurality of hydrogel spring ring
Later, due to its mechanical state with flexible relative, gel can closely tangle in the blood vessels, to promote filling rate, shut out
The generation led to again absolutely.
Summary of the invention
The present invention overcomes deficiencies in the prior art, cause acrylonitrile, acrylamide and polyethylene glycol by free radical
Dimethylacrylate (PEG3kDMA, number-average molecular weight 3000) cross-linked polymeric in dimethyl sulfoxide (DMSO), with molten
After agent exchange removes organic solvent and do not reflect the small molecule of completion, upper barium sulfate is deposited in network, one kind is prepared can X
The high-modulus of photodevelopment, high-intensitive body temperature stimulation shape memory gel simultaneously can make spring ring.
The purpose of the present invention is achieved by following technical proposals.
The body temperature stimulation shape memory gel that can be used for hemangioma embolism, using acrylonitrile, acrylamide as comonomer,
Using polyethylene glycol dimethacrylate as crosslinking agent, cause comonomer and crosslinking agent using initiator in solvent atmosphere
Unsaturated bond is copolymerized, will the obtained product of copolymerization be immersed in it is fixed-type in phosphate buffer solution after, be dipped into respectively
In barium chloride and aqueous sodium persulfate solution, so that barium sulfate deposits in hydrogel network.
The mass ratio of acrylonitrile and acrylamide is (1-5): 1, preferably (2-3): 1.
Crosslinking agent accounts for (10-15) wt% of acrylonitrile Yu acrylamide gross mass, and preferably crosslinking agent accounts for acrylonitrile and propylene
(12-14) wt% of amide gross mass.
Overall solid content is (20-30) wt%, and preferably 24-28wt%, overall solid content is (comonomer and crosslinking agent
Quality sum)/(quality sum of comonomer, crosslinking agent and solvent).
Polyethylene glycol dimethacrylate number-average molecular weight is 500-3000, preferably 1000-3000.
It in the inventive solutions, should be according to comonomer, crosslinking agent, the dissolution for causing system (containing initiator)
Property, the solvent that can be completely dissolved above-mentioned substance or can dissolve each other completely with above-mentioned substance is selected, to be uniformly mixed reactant
System.In view of comonomer polarized, and initiation system and crosslinking agent are also wanted to be dissolved in polar solvent, therefore may be selected
Polar solvent in organic solvent, such as dimethylformamide, dimethyl acetamide, tetrahydrofuran, dimethyl sulfoxide.
In the inventive solutions, using acrylonitrile, acrylamide as comonomer, with polyethylene glycol dimethyl allene
Acid esters is crosslinking agent (strand both ends are with the backbone structure for being peg molecule) among double bond, strand, using initiation
Agent provides free radical, causes the unsaturated bond (i.e. carbon-carbon double bond) of comonomer and crosslinking agent, makes three almost while causing hair
Raw polymerization reaction, finally prepares hydrogel.With polyacrylonitrile, polyacrylamide and crosslinking agent three kinds of substances in hydrogel
Segment, acrylonitrile provide the rigid nature in skeleton, and acrylamide provides the toughness properties in skeleton, and crosslinking agent provides flexible chain
Section, this few part synergistic effect, so that entire hydrogel material shows excellent mechanical property and temperature sensitivity and shape
Shape memory function.
Before initiator causes polymerization, reactant is excluded using inert protective gas (such as nitrogen, argon gas or helium)
Oxygen in system, to avoid its inhibition.Initiator selects to commonly use thermal initiator, such as ammonium persulfate in field of macromolecule polymerization
(APS), potassium peroxydisulfate (KPS), benzoyl peroxide (BPO), azobisisoheptonitrile (ABIN), initiator amount is comonomer
With (0.2-1.0) % of crosslinking agent gross mass, preferably 0.5-0.8%, be warming up to initiation temperature or more, and keep quite long
Time, such as 20-40h, to promote initiator that can generate enough free radicals for a long time, initiation reaction system persistently occurs
Raolical polymerizable finally prepares hydrogel of the invention；Or photoinitiator, such as 2- hydroxy-2-methyl -1- phenyl -1-
Acetone (Irgacure 1173), initiator amount be comonomer and crosslinking agent gross mass (0.2-1.0) %, preferably 0.5-
0.8%, transparent closed reaction vessel is selected, causes free radical polymerization under conditions of ultraviolet light, due to light-initiated effect
Rate causes higher than heat, and when adjusting irradiation time because of the activity and dosage of the initiator according to selected by, irradiation time can shorter than heat cause
Heating time, such as 1-5h；Or cause system, such as by initiator benzoyl peroxide (BPO) and rush initiator N, N- diformazan
The initiation system of base aniline (DMA) composition, initiator amount is (0.2-1.0) % of comonomer and crosslinking agent gross mass, excellent
0.5-0.8% is selected, promoting initiator n,N-Dimethylaniline (DMA) dosage is initiator benzoyl peroxide (BPO) quality
(8-12) %, 20-30 degrees Celsius of room temperature can initiation reaction, react 20-30h.
When carrying out impregnating fixed-type, selection is immersed in 20-30 DEG C of phosphate buffer (PBS, pH are 7-7.4)
It is fixed, preferably it is fixed as spring shape.
When carrying out immersion blanc fixe, fixed-type hydrogel is impregnated the barium chloride of 5-8mol/L by selection respectively
Each 5-8h of aqueous sodium persulfate solution of aqueous solution, 5-8mol/L repeats to impregnate 2-5 times.
After the preparation, the hydrogel of blanc fixe phosphate buffer (PBS, pH are 7-7.4) is impregnated again to remove
Decontamination obtains body temperature stimulation shape memory gel (such as spring ring) that can be used for hemangioma embolism.
It specifically prepares the method for hydrogel spring ring, carries out as steps described below:
Step 1, acrylonitrile, acrylamide and crosslinking agent polyethylene glycol dimethacrylate (PEG3kDMA) are added to
In dimethyl sulfoxide (DMSO), be placed in dissolution in centrifuge tube, mixture in vortex centrifugal pipe until obtain clear solution, by
Nitrogen is carried out to above-mentioned solution at room temperature and is bubbled 8-12min, removes oxygen, to prevent polymerization inhibitor, when finally by nitrogen flushing gas bell
Initiator benzoyl peroxide (BPO) is added and promotees initiator n,N-Dimethylaniline (DMA), for causing polymerization-filling,
In, the mass ratio of acrylonitrile and acrylamide is (1-3): 1, crosslinking agent accounts for (10-15) of acrylonitrile Yu acrylamide gross mass
Wt%, overall solid content are (20-30) wt%, and benzoyl peroxide (BPO) is (0.2- of monomer and crosslinking agent gross mass
1.0) %, n,N-Dimethylaniline (DMA) are (8-12) % of benzoyl peroxide (BPO) quality；
Step 2, reaction solution step 1 being prepared, which is placed in tetrafluoroethene capillary, to be polymerize, and reaction temperature is
It 20-30 DEG C, after the reaction time is 20-30h, after removing tetrafluoroethene capillary taking-up gel batten, is wound on rod iron, is led to
It crosses to be immersed in 20-30 DEG C of phosphate buffer (PBS, selecting pH is 7-7.4) and is fixed as spring shape, obtain hydrogel bullet
Spring coil；
Step 3, the hydrogel spring ring that step 2 is prepared is impregnated into the barium chloride solution of 5-8mol/L, 5- respectively
Each 5-8h of the aqueous sodium persulfate solution of 8mol/L is repeated 2-5 times, barium sulfate is deposited in gel network, is then soaked again
It steeps phosphate buffer (PBS) and removes impurity, obtain the body temperature stimulation shape memory gel spring that can be used for hemangioma embolism
Circle.
In step 2, the temperature of polymerization reaction is 20-25 DEG C of room temperature, and time of polymerization reaction is 20-for 24 hours.
In step 2, it is 1-1.5mm, length 0.8-1.2m, the ruler of rod iron that the size of tetrafluoroethene capillary, which is diameter,
Very little is long (8-12) cm, diameter is (0.8-1.2) mm, and soaking process is to replace a phosphate buffer every (10-12) h
(PBS), total immersion is steeped 5-10 days, to displace organic solvent, remove residual monomer and initiator.
In step 3, the concentration of barium chloride solution is 6mol/L, and aqueous sodium persulfate solution concentration is 6mol/L, when immersion
Between be respectively 6h, in triplicate.
As shown in Figure 1 (in figure arrow pointed location be partial enlargement appearance), the gel prepared in DMSO is (i.e. organic
Gel) and the gel (i.e. hydrogel) that is obtained by DMSO and PBS environment replacement Treatment prepare sample according to identical standard, cut out
After dumbbell shape sample (effective length 10mm, wide 2mm, thickness 0.5mm), is stretched, obtained using the strain rate of 100mm/min
Hydrogel Young's modulus be 14-18MPa, fracture strength 10-15MPa, much higher than the intensity of organogel, it was demonstrated that in water-setting
The not only copolymerization network of comonomer and crosslinking agent in glue, the physical crosslinking being made of dipole effect and hydrogen bond is equally well
Toughening hydrogel.As shown in Fig. 2, the gel batten of wide 6-7mm, thickness 1.2mm are fixed on submergence stretching clamp by a length of 20mm
Upper (instrument model Q800, TA company, the U.S.), with the pretightning force of 0.01N, 5 microns of amplitude, 1 hertz frequency carries out dynamic mechanical
Test, heating rate are 2 DEG C.This figure proves that the modulus of hydrogel has very strong temperature dependency, the variation of loss angle tangent
Also the mechanical behavior for disclosing gel is presented different viscoelastic sexual behaviour with temperature, i.e., sample in certain temperature section from
Start to soften to complete softening, such as 25-40 degrees Celsius.As shown in figure 3, carrying out hydrogel precipitated barium sulfate using same procedure
The performance test of front and back, precipitated barium sulfate is several to the mechanics and temperature dependency mechanical behavior of hydrogel as can be seen from Figure
Do not influence.
The spring ring prepared using subject hydrogel is subjected to shape memory test, the spring ring under 37 degrees Celsius is drawn
Shape is carried out at 20 degrees celsius after straight to fix, and is subsequently placed in 37 DEG C waters and is observed, as shown in figure 4, by can in figure
To find out that hydrogel spring ring can complete the transfer of shapes for becoming spring from vertical bar in 5 seconds.By the sample being straightened by leading
Pipe is deep into the arteria renalis of BaMa miniature pig, and since body temperature increases, discovery hydrogel spring ring has good in vivo
Development effect, and the shape memory effect of anticipation can be completed, spring loop-shaped is restored by straight condition, as shown in Figure 5.Into one
Step, after a plurality of hydrogel batten (3-4) is delivered to the arteria renalis of bull BaMa miniature pig, increased using body temperature real
The shape memory of existing volume restores, and the embolism of the arteria renalis is realized, and 4 weeks behind, 8 weeks, 12 weeks are checked, such as Fig. 6 institute
Show, hydrogel Coil embolization effect prepared by the present invention is very stable as can be seen from Figure, does not find to lead to phenomenon again.That is this hair
Bright hydrogel is preparing the application in X development embolism materials.
The invention has the benefit that preparation method is simple, the embolism spring ring of water-setting matrix is prepared for the first time, is improved
The defect of the low Yi Chongtong of commercial metal spring ring filling rate；Body temperature is the stimulus of shape memory effect, and biology is friendly；Hydrogel
Modulus under room temperature is high, can directly be pushed；In-situ deposition barium sulfate make gel can X-ray development, and possess shape note
Recall effect.
Detailed description of the invention
Fig. 1 is the Mechanics Performance Testing figure for the hydrogel that the present invention is prepared；
Fig. 2 is the temperature dependency mechanical behavior test chart for the hydrogel that the present invention is prepared；
Fig. 3 is that precipitated barium sulfate surveys the mechanics and temperature dependency mechanical behavior of the hydrogel of the invention being prepared
Attempt；
Fig. 4 is the shape memory testing in vitro figure for the hydrogel spring ring that the present invention is prepared；
Fig. 5 is the shape memory internal test figure for the hydrogel spring ring that the present invention is prepared；
Fig. 6 be a plurality of hydrogel batten is delivered to after the arteria renalis of BaMa miniature pig realize embolism after 4 weeks, 8 weeks, 12 weeks
Check X-ray picture.
Specific embodiment
Below by specific embodiment, further description of the technical solution of the present invention.
Embodiment 1
Step 1,0.5g acrylamide is weighed with assay balance respectively, 0.1875g polyethylene glycol dimethacrylate is put
In 10ml centrifuge tube, then with liquid-transfering gun measure 5.063ml DMSO be completely dissolved after, the acrylonitrile of 1ml is added, then
The BPO of 0.0075g is added, mixes again, leads to nitrogen 10min deoxygenation.
Step 2, after the DMA mixing of 1 μ L is added, solution in centrifuge tube is pumped into capillary with 10ml syringe at once,
And sealed both ends with haemostatic clamp, it places it in 25 DEG C of insulating boxs and takes out afterwards for 24 hours.
Step 3, tetrafluoroethene capillary is then torn, it is careful to take out gel batten, it is wrapped in long 10cm, diameter is
On the rod iron of 1mm, spring shape is fixed as by being immersed in 25 DEG C of phosphate buffers (PBS).Above-mentioned soaking process needs every
A PBS is replaced every 12h, total immersion is steeped 7 days, to displace organic solvent, remove residual monomer and initiator.
Step 4, then the sodium sulphate water that hydrogel spring ring impregnates the barium chloride solution of 6mol/L, 6mol/L respectively is obtained
Each 6h of solution in triplicate deposits to barium sulfate in gel network, then impregnates PBS again and removes impurity, can be used for
The body temperature of hemangioma embolism stimulates shape memory gel spring ring.
Embodiment 2
Step 1,0.5g acrylamide is weighed with assay balance respectively, 0.2g polyethylene glycol dimethacrylate is placed on
In 10ml centrifuge tube, then with liquid-transfering gun measure 5.0ml DMSO be completely dissolved after, the acrylonitrile of 1.5ml is added, then plus
The BPO for entering 0.0075g, mixes again, leads to nitrogen 12min deoxygenation.
Step 2, after the DMA mixing of 0.6 μ L is added, solution in centrifuge tube is pumped into capillary with 10ml syringe at once
In, and sealed both ends with haemostatic clamp, it places it in 22 DEG C of insulating boxs and is taken out after 26h.
Step 3, tetrafluoroethene capillary is then torn, it is careful to take out gel batten, it is wrapped in long 12cm, diameter is
On the rod iron of 1.2mm, spring shape is fixed as by being immersed in 25 DEG C of phosphate buffers (PBS).Above-mentioned soaking process needs
A PBS is replaced every 10h, total immersion is steeped 10 days, to displace organic solvent, remove residual monomer and initiator.
Step 4, then the sodium sulphate water that hydrogel spring ring impregnates the barium chloride solution of 5mol/L, 8mol/L respectively is obtained
Each 5h of solution, repeats five times, barium sulfate is deposited in gel network, then impregnates PBS again and removes impurity, can be used for
The body temperature of hemangioma embolism stimulates shape memory gel spring ring.
Embodiment 3
Step 1,0.5g acrylamide is weighed with assay balance respectively, 0.15g polyethylene glycol dimethacrylate is placed on
In 10ml centrifuge tube, then with liquid-transfering gun measure 5.1ml DMSO be completely dissolved after, the acrylonitrile of 0.5ml is added, then plus
The BPO for entering 0.0075g, mixes again, leads to nitrogen 8min deoxygenation.
Step 2, after the DMA mixing of 1.2 μ L is added, solution in centrifuge tube is pumped into capillary with 10ml syringe at once
In, and sealed both ends with haemostatic clamp, it places it in 26 DEG C of insulating boxs and is taken out after 22h.
Step 3, tetrafluoroethene capillary is then torn, it is careful to take out gel batten, it is wrapped in long 8cm, diameter is
On the rod iron of 0.8mm, spring shape is fixed as by being immersed in 25 DEG C of phosphate buffers (PBS).Above-mentioned soaking process needs
A PBS is replaced every 9h, total immersion is steeped 5 days, to displace organic solvent, remove residual monomer and initiator.
Step 4, then the sodium sulphate water that hydrogel spring ring impregnates the barium chloride solution of 8mol/L, 5mol/L respectively is obtained
Each 8h of solution, is repeated twice, barium sulfate is deposited in gel network, then impregnates PBS again and removes impurity, can be used for
The body temperature of hemangioma embolism stimulates shape memory gel spring ring.
The preparation of subject hydrogel can be achieved in the technological parameter and formula that content is recorded according to the present invention, and shows
Almost the same performance.Illustrative description is done to the present invention above, it should which explanation is not departing from core of the invention
In the case where, any simple deformation, modification or other skilled in the art can not spend being equal for creative work
Replacement each falls within protection scope of the present invention.
Claims (10)
1. can be used for the body temperature stimulation shape memory gel of hemangioma embolism, which is characterized in that be with acrylonitrile, acrylamide
Comonomer causes comonomer using initiator in solvent atmosphere using polyethylene glycol dimethacrylate as crosslinking agent
Be copolymerized with the unsaturated bond of crosslinking agent, will the obtained product of copolymerization be immersed in it is fixed-type in phosphate buffer solution after,
It is dipped into barium chloride and aqueous sodium persulfate solution respectively, so that barium sulfate deposits in hydrogel network, wherein acrylonitrile and third
The mass ratio of acrylamide is (1-5): 1, crosslinking agent accounts for (10-15) wt% of acrylonitrile Yu acrylamide gross mass, overall to contain admittedly
Amount is (20-30) wt%.
2. the body temperature stimulation shape memory gel according to claim 1 that can be used for hemangioma embolism, which is characterized in that
The mass ratio of acrylonitrile and acrylamide is (2-3): 1, crosslinking agent accounts for (12-14) of acrylonitrile Yu acrylamide gross mass
Wt%, overall solid content are 24-28wt%；Polyethylene glycol dimethacrylate number-average molecular weight is 500-3000, preferably
1000—3000。
3. the body temperature stimulation shape memory gel according to claim 1 that can be used for hemangioma embolism, which is characterized in that
When carrying out impregnating fixed-type, selection is immersed in 20-30 DEG C of phosphate buffer (PBS, pH are 7-7.4) and fixes, preferably
It is fixed as spring shape；When carrying out immersion blanc fixe, fixed-type hydrogel is impregnated 5-8mol/L by selection respectively
Barium chloride solution, 5-8mol/L each 5-8h of aqueous sodium persulfate solution, repeat impregnate 2-5 times.
4. the body temperature stimulation shape memory gel according to claim 1 that can be used for hemangioma embolism, which is characterized in that
Solvent is dimethylformamide, dimethyl acetamide, tetrahydrofuran, dimethyl sulfoxide.
5. the body temperature stimulation shape memory gel according to claim 1 that can be used for hemangioma embolism, which is characterized in that
Before initiator causes polymerization, the oxygen in reaction system is excluded using inert protective gas (such as nitrogen, argon gas or helium),
To avoid its inhibition.Initiator selects to commonly use thermal initiator in field of macromolecule polymerization, such as ammonium persulfate (APS), mistake
Potassium sulfate (KPS), benzoyl peroxide (BPO), azobisisoheptonitrile (ABIN), initiator amount are comonomer and crosslinking agent
(0.2-1.0) % of gross mass, preferably 0.5-0.8%, it is warming up to initiation temperature or more, and keep for quite a long time, such as
20-40h, to promote initiator that can generate enough free radicals for a long time, radical polymerization persistently occurs for initiation reaction system
Reaction is closed, hydrogel of the invention is finally prepared；Or photoinitiator, such as 2- hydroxy-2-methyl -1- phenyl -1- acetone
(Irgacure 1173), initiator amount be comonomer and crosslinking agent gross mass (0.2-1.0) %, preferably 0.5-
0.8%, transparent closed reaction vessel is selected, causes free radical polymerization under conditions of ultraviolet light, due to light-initiated effect
Rate causes higher than heat, and when adjusting irradiation time because of the activity and dosage of the initiator according to selected by, irradiation time can shorter than heat cause
Heating time, such as 1-5h；Or cause system, such as by initiator benzoyl peroxide (BPO) and rush initiator N, N- diformazan
The initiation system of base aniline (DMA) composition, initiator amount is (0.2-1.0) % of comonomer and crosslinking agent gross mass, excellent
0.5-0.8% is selected, promoting initiator n,N-Dimethylaniline (DMA) dosage is initiator benzoyl peroxide (BPO) quality
(8-12) %, 20-30 degrees Celsius of room temperature can initiation reaction, react 20-30h.
6. can be used for hemangioma embolism body temperature stimulation shape memory gel preparation method, which is characterized in that with acrylonitrile,
Acrylamide is comonomer, using polyethylene glycol dimethacrylate as crosslinking agent, is drawn in solvent atmosphere using initiator
The unsaturated bond of hair comonomer and crosslinking agent is copolymerized, and the product that copolymerization obtains is immersed in phosphate buffer solution solid
After fixed molding, it is dipped into barium chloride and aqueous sodium persulfate solution respectively, so that barium sulfate deposits in hydrogel network, wherein third
The mass ratio of alkene nitrile and acrylamide is (1-5): 1, crosslinking agent accounts for (10-15) wt% of acrylonitrile Yu acrylamide gross mass,
Overall solid content is (20-30) wt%；
7. the preparation method of the body temperature stimulation shape memory gel according to claim 6 that can be used for hemangioma embolism,
It is characterized in that, selection is immersed in 20-30 DEG C of phosphate buffer when carrying out impregnating fixed-type (PBS, pH are 7-7.4)
Middle fixation is preferably fixed as spring shape；When carrying out immersion blanc fixe, fixed-type hydrogel is soaked respectively by selection
The barium chloride solution of 5-8mol/L, each 5-8h of aqueous sodium persulfate solution of 5-8mol/L are steeped, repeats to impregnate 2-5 times.
8. the preparation method of the body temperature stimulation shape memory gel according to claim 6 that can be used for hemangioma embolism,
It is characterized in that, the mass ratio of acrylonitrile and acrylamide is (2-3): 1, crosslinking agent accounts for acrylonitrile and acrylamide gross mass
(12-14) wt%, overall solid content be 24-28wt%；Polyethylene glycol dimethacrylate number-average molecular weight is 500-
3000, preferably 1000-3000；Solvent is dimethylformamide, dimethyl acetamide, tetrahydrofuran, dimethyl sulfoxide.
9. the preparation method of the body temperature stimulation shape memory gel according to claim 6 that can be used for hemangioma embolism,
It is characterized in that, excluding to react using inert protective gas (such as nitrogen, argon gas or helium) before initiator causes polymerization
Oxygen in system, to avoid its inhibition.Initiator selects to commonly use thermal initiator, such as persulfuric acid in field of macromolecule polymerization
Ammonium (APS), potassium peroxydisulfate (KPS), benzoyl peroxide (BPO), azobisisoheptonitrile (ABIN), initiator amount are that copolymerization is single
(0.2-1.0) % of body and crosslinking agent gross mass, preferably 0.5-0.8%, it is warming up to initiation temperature or more, and keep considerably long
Time, such as 20-40h, to promote initiator that can generate enough free radicals for a long time, initiation reaction system is persistently sent out
Raw Raolical polymerizable, finally prepares hydrogel of the invention；Or photoinitiator, such as 2- hydroxy-2-methyl -1- phenyl -
1- acetone (Irgacure 1173), initiator amount are (0.2-1.0) % of comonomer and crosslinking agent gross mass, preferably
0.5-0.8%, transparent closed reaction vessel is selected, causes free radical polymerization under conditions of ultraviolet light, since light draws
Efficiency is sent out higher than heat initiation, when adjusting irradiation time because of the activity and dosage of the initiator according to selected by, irradiation time can be shorter than hot
The heating time of initiation, such as 1-5h；Or cause system, such as by initiator benzoyl peroxide (BPO) and rush initiator N, N-
The initiation system of dimethylaniline (DMA) composition, initiator amount are the (0.2- of comonomer and crosslinking agent gross mass
1.0) %, preferably 0.5-0.8%, rush initiator n,N-Dimethylaniline (DMA) dosage are initiator benzoyl peroxide
(BPO) (8-12) % of quality, 20-30 degrees Celsius of room temperature can initiation reaction, react 20-30h.
10. prepared by the body temperature stimulation shape memory gel that can be used for hemangioma embolism as described in one of claim 1-5
Application in X development embolism materials, which is characterized in that preferable shape is spring ring.
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