CN106267324A - A kind of temperature response type macromolecule bio-medical adhesive and synthetic method thereof - Google Patents
A kind of temperature response type macromolecule bio-medical adhesive and synthetic method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/30—Compositions for temporarily or permanently fixing teeth or palates, e.g. primers for dental adhesives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
- A61K6/884—Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
- A61K6/891—Compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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- 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
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
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Abstract
The present invention provides temperature response type macromolecule bio-medical adhesive and preparation thereof in one, belongs to and uses glue material technical field.The present invention is with polyhydroxy or polyamino dissaving polymer as initiator; with oxolane as solvent; the aminoacid of N carbonyl inner-acid anhydride is had as function monomer with end; nitrogen is protected; reacting 48 ~ 72h in polymerized at room temperature, after reaction terminates, the crude product mixed solution of triethylamine ethanol precipitates; the high-molecular biologic medical adhesive obtained is when 37 ± 0.5 DEG C, and bond strength is between 90 ~ 130 Kpa.It addition, high-molecular biologic medical adhesive of the present invention is with amino acid needed by human body as raw material, therefore have good biocompatibility, have no side effect, can be degraded in tissue metabolism.
Description
Technical field
The present invention relates to a kind of medical adhesive, particularly relate to a kind of temperature response type macromolecule bio-medical adhesive and
Its synthetic method, belongs to polymeric material field and field of biomedical materials.
Background technology
Medical adhesive is the biomedical material that a class is novel, the most replaces suture with multiple otch adhesive,
Its advantage is convenient, fast, need not take out stitches, and after wound healing, cicatrix is the least.Medical adhesive kind a lot, according to purposes
Soft tissue can be divided into stick with glue agent, dental adhesive, bone cement and skin adhesive etc..Soft tissue sticks with glue agent clinic should
Have a-cyanoacrylate, fibrin and polyurethane adhesive.But these adhesive also have some to be difficult to overcome
Shortcoming, although the time is short, quick solidifying such as a-cyanoacrylate bonding, but glue-line fragility is strong, intensity is low and catabolic process
Formaldehyde can be produced；Although fibrin biocompatibility, haemostatic effect are good, but intensity is low, easy to leak.By contrast, high score
Sub-hydrogel had both had hemostatic analgesia effect, it may have good biocompatibility, elasticity and intensity.Therefore, macromolecule water-setting
Glue is gradually paid attention to by researcher as the research of soft tissue adhesive.Inspired by Mollusca mussel, by catechol
Functional group is incorporated in macromolecular chain, is formed in situ aquogel system by chemical crosslinking, has good tissue adhesion effect,
Can be used for the bonding of the soft tissue such as intestinal, skin.This kind of aquogel system reported has modification of chitosan/Polyethylene Glycol, modification
Chitosan/Polyether, chitosan/3,4-dihydroxy benzenes propanoic acid, Polyethylene Glycol/polycaprolactone/dihydroxy benzenes propanoic acid, citric acid/poly-
Ethylene glycol/dopamine etc..It is respectively increased compared to business-like medical adhesive, fracture strength and tensile strength and has carried more greatly
High.As Mathiowitz etc. reports a kind of polyacrylic acid derivative aquogel type gluing with dihydroxyphenylalanine side base
Agent, tests through live body rat intestine adhesion test, and fracture strength and the tensile strength of this new adhesive have been respectively increased 2.5 Hes
2.8 again.In addition to class dopamine structure, guanidine radicals and phosphocholine are all the biological organo-functional groups with electric charge, can be with tissue
Protein chain generation charge effect, thus also can be utilized for medical science bonding.Okuro etc. have synthesized a kind of water with nine guanidine radicals
Dissolubility dendrimer, can in situ with histone effect and gelation, be a kind of typical " molecule glue ".Yu etc. are tree-shaped poly-
The end group of ethylene glycol modifies upper phosphocholine fragment, and it can form class biomembrane, good biocompatibility, wound healing when bonding
Hurry up.Additionally, Strehin etc. with N-hydroxy-succinamide by the carboxyl esterification of chondroitin sulfate, then with primary amine reaction, and then with
The Amino End Group Polyethylene Glycol of six arms forms hydrogel as cross-linking agent, and it can be combined with the amino covalence of histone, reaches viscous
The purpose closed.Chitosan and the modified starch (oxidising maltose dextrin) such as Serrero are used for organizing adhesion as adhesive.So
And, these aquogel type adhesives yet suffer from or solidify relatively slow or intensity not enough or easily occurs leakage of body fluids etc. many not
Foot, still needs to improve further.
Summary of the invention
It is an object of the invention to the deficiency existed for existing medical adhesive, it is provided that a kind of curing rate is fast, degradability
Can be good, the temperature response type macromolecule bio-medical adhesive that bond strength is high；
It is a further object of the present invention to provide the synthetic method of said temperature response polymer bio-medical adhesive.
One, the synthesis of temperature response type macromolecule bio-medical adhesive
The present invention is with polyhydroxy or polyamino dissaving polymer as initiator, with oxolane as solvent, has N-with end
The aminoacid of carbonyl inner-acid anhydride (NCA) is function monomer, and nitrogen is protected, and reacts 48 ~ 72h in polymerized at room temperature, after reaction terminates, slightly
The mixed solution of product triethylamine-ethanol precipitates and obtains.
Described end has the aminoacid of N-carbonyl inner-acid anhydride (NCA) to be Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl
Base inner-acid anhydride (Glu-EG2-NCA), L-3,4-dihydroxy benzenes methyl aminoacetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA), essence ammonia
Acid-N-carbonyl inner-acid anhydride (Arg-NCA), cysteine-N-carbonyl inner-acid anhydride (Cys-NCA) or ε-N acrylamide lysine-
At least two in N-carbonyl inner-acid anhydride (AM-Lys-NCA).
Described polyhydroxy dissaving polymer is to react with BDO and metallic potassium to cause epoxy prapanol open loop, obtains
Hyperbranched polyglycidyl ether, adds metallic potassium, the hyperbranched polyhydroxylated polymer potassium alcoholate that reaction obtains.
Document S. Roller, H. Zhou, R. Haag, Mol Divers are shown in the synthesis of hyperbranched polyglycidyl ether
2005,9,305.), its structure is:
The structure of hyperbranched polyhydroxylated polymer potassium alcoholate is:
。
Described polyamino dissaving polymer is ultrabranching polyamide-amine, its product grade: CYD-130A.
Described initiator is 1:620 ~ 1:1030 with the mole of function monomer (total amount).
Described function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride (Glu-EG2-NCA),
During L-3,4-dihydroxy benzenes methyl aminoacetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA), the mol ratio of the two is 1:0.9 ~ 1:
1.1。
Described function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride (Glu-EG2-NCA),
L-3,4-dihydroxy benzenes methyl aminoacetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA), arginine-N-carbonyl inner-acid anhydride (Arg-
NCA), time, the mol ratio of three is 1:0.9:0.58 ~ 1:1.1:0.63.
Described function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride (Glu-EG2-NCA),
L-3,4-dihydroxy benzenes methyl aminoacetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA), arginine-N-carbonyl inner-acid anhydride (Arg-
NCA), cysteine-N-carbonyl inner-acid anhydride (Cys-NCA) time, the mol ratio of four is 1:0.9:0.58:0.58 ~ 1:1.1:
0.63:0.63。
Described function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride (Glu-EG2-NCA),
L-3,4-dihydroxy benzenes methyl aminoacetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA), arginine-N-carbonyl inner-acid anhydride (Arg-
NCA), ε-N acrylamide lysine-N-carbonyl inner-acid anhydride (AM-Lys-NCA) time, the mol ratio of four is 1:0.9:0.58:
0.58~1:1.1:0.63:0.64。
Two, the performance of temperature response type bio-medical adhesive
1, Thermo-sensitive test
Method of testing: lowest critical solution temperature (LCST) is the important characterization parameter of the temperature sensitive performance of polymer.Poly-by measuring
The curve that the light transmittance of polymer solution varies with temperature, takes the temperature corresponding when light transmittance drops to initial light transmittance 50% fixed
Justice is its LCST value.The temperature sensitive performance of polymer is relative equilibrium based on polymer hydrophilicity Yu hydrophobicity effect.Compound concentration
For the aqueous solutions of polymers of 0.3mg/mL, by ultraviolet-uisible spectrophotometer (UV-VIS) at 500 nm, measure not equality of temperature
The light transmittance change curve of the lower solution of degree, thus obtain its LCST value.
Measurement result: by measuring the curve that varies with temperature of light transmittance of polymer solution, it is possible to obtain it is minimum faces
Boundary's solution temperature (LCST), Fig. 1 is the printing opacity of the adhesive solution prepared as initiator with hyperbranched polyhydroxylated polymer potassium alcoholate
Rate varies with temperature curve.From Fig. 1, we can see that the LCST value of this base polymer is about 33 DEG C.Fig. 2 is with over-expense
The light transmittance changing the adhesive solution that polyamide-amide is prepared as initiator varies with temperature curve.We can see that from Fig. 2
The LCST value of this base polymer is about 31 DEG C.
2, bond performance test
Bond strength testing method: Corii Sus domestica first cleans with the sodium chloride solution of 0.9%, then soaks with the PBS of pH=7.4
At night, it is used for testing.Being dissolved in the PBS of pH=7.4 by the polymer of gained, being formulated as mass fraction is 10%, then will
In its horseradish peroxidase being dissolved in 0.06 mg/mL respectively and hydrogenperoxide steam generator that mass fraction is 0.06%, use respectively
In two pieces of pig skin surfaces, then two pieces of Corii Sus domesticas are forced together, give certain pressure simultaneously, use ASTM testing standard, by 10
The speed of mm/min carries out coherent Corii Sus domestica, until pulling open, records data, parallel survey three groups.
Test result: Fig. 3 is the bond strength test result of adhesive solution prepared by embodiment 1-4.By Fig. 3, Fig. 4
Test result finds, along with the increase of testing time, prepared adhesive bond strength is gradually increasing.Simultaneously along with introducing merit
The increase of energy monomeric species, the adhesive bond strength obtained also is gradually increasing.This is due to the guanidine radicals cation in arginine
Electric charge can be occurred to overlap with the carboxyl in protein etc. and produce crosslinking, the sulfydryl in cysteine can with in protein
Sulfydryl generation oxidation reaction generates disulfide bond, and the sulfydryl in cysteine and the double bond in acrylamide lysine can occur simultaneously
Click-reaction so that it is bond strength improves.
Fig. 5 is the bond strength test respectively under conditions of 25 DEG C and 37 DEG C of the adhesive solution prepared of embodiment 1-4
Result.Fig. 6 is the adhesive solution prepared of embodiment 5-8 bond strength test knot respectively under conditions of 25 DEG C and 37 DEG C
Really.Found by the test result of Fig. 5, Fig. 6, the solidification rate of adhesive substantially fast than 25 DEG C when 37 DEG C.It is due at this thing
Introducing diethylene glycol monomethyl ether in matter, the adhesive making us obtain has temperature-responsive, thus when temperature reaches 37 DEG C
Time, this adhesive solidifies rapidly, is possible to prevent leakage of body fluids.And 37 DEG C is normal human body temperature, so this invention is suitable as
Medical adhesive.
In sum, the present invention is with the hyperbranched potassium alcoholate of polyhydroxy or ultrabranching polyamide-amine as initiator, with L-paddy ammonia
Acid-β-diethylene glycol monomethyl ether ester (Glu-EG2) and the residue of 3,4-dihydroxyphenylalanine (DOPA) as gluing group
Dissaving polymer adhesive HPGMD, on the basis of adhesive HPGMD, for improving solidification rate and adhesion strength, introduces essence
Propylhomoserin fragment, obtains adhesive HPGMDA/PAMAMGMD；For improving adhesion strength further, at adhesive HPGMDA/
On the basis of PAMAMGMDA, introduce cysteine fragment and acrylated lysine blockage respectively, obtain adhesive
HPGMDAC/PAMAMGMDAC and HPGMDAL/PAMAMGMDAL, this adhesive can mix the most immediately.Above-mentioned adhesive
Performance be better than document report the overwhelming majority be similar to biomimetic polymer adhesive.This is owing to the guanidine radicals in arginine can be with
Carboxyls in protein etc. cross-link, and the sulfydryl in cysteine can generate with the sulfydryl generation oxidation reaction in protein
Disulfide bond, the sulfydryl in cysteine and the double bond in acrylamide lysine can occur click-reaction simultaneously so that it is tension is strong
Degree strengthens.It addition, this adhesive is with amino acid needed by human body as raw material, therefore there is good biocompatibility, nontoxic pair
Act on, can be degraded in tissue metabolism.
Accompanying drawing explanation
Fig. 1 is that the light transmittance of the adhesive solution prepared as initiator with hyperbranched polyhydroxylated polymer potassium alcoholate becomes with temperature
Change curve.Fig. 2 is that the light transmittance of the adhesive solution prepared as initiator with ultrabranching polyamide-amine varies with temperature curve.
Fig. 3 is the bond strength test result of adhesive solution prepared by embodiment 1-4.
Fig. 4 is the bond strength test result of adhesive solution prepared by embodiment 5-8.
Fig. 5 is the bond strength test respectively under conditions of 25 DEG C and 37 DEG C of the adhesive solution prepared of embodiment 1-4
Result.
Fig. 6 is the bond strength test respectively under conditions of 25 DEG C and 37 DEG C of the adhesive solution prepared of embodiment 5-8
Result.
Detailed description of the invention
Below by specific embodiment, synthetic method and the performance of temperature response type bio-medical adhesive of the present invention are done
Further illustrate.
Embodiment 1:HP (DOPA-Glu-EG2) preparation
Glu-EG2Preparation: at 50 mL equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection device
Three-neck flask adds 2.5 g(16.99mmol) glutamic acid and 15mL(129.21mmol) diethylene glycol monomethyl ether, by 2 mL
Concentrated sulphuric acid joins in constant pressure funnel, protects at nitrogen, is slowly added in three-neck flask under ice bath under conditions of 0 DEG C
React 12 h, obtain crude product.Crude product is poured in the mixture of 50 mL triethylamines and 50 mL ethanol, obtain white heavy
Form sediment, centrifugal, by the 10mL methanol dissolving of the white precipitate of institute into, then solution is poured the white precipitate in the ether of 100mL, from
The heart, gained white precipitate product, vacuum drying, obtain white solid and be Pidolidone-β-diethylene glycol monomethyl ether ester (Glu-
EG2), productivity is 55%.
The preparation of Glu-EG2-NCA: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection dress
The 100 mL three-neck flasks put add 1 g(4.02mmol) Glu-EG2And oxolane 30 mL through Non-aqueous processing,
Constant pressure funnel adds 10 mL dissolved with 1.94 g(6.54mmol) tetrahydrofuran solution of triphosgene.It is warming up to 50 DEG C of left sides
The right side, is slowly added into the triphosgene solution in constant pressure funnel in three-neck flask under magnetic stirring.React to solution one-tenth
For reacting 30 min after light yellow transparent solution again.At this moment lead to nitrogen to be brought into remaining triphosgene and HCl gas containing full
With in the absorption plant of NaOH solution.After tail gas absorption processes, concentration of reaction solution, add appropriate normal hexane, stand, have
Faint yellow solid separates out, and is filtrated to get crude product.Crude product normal hexane and re-crystallizing in ethyl acetate, obtain white crystal and be
Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride (Glu-EG2-NCA).
The preparation of DOPA-NCA: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection device
50mL three-neck flask adds 0.5g(2.54mmol) 3,4-dihydroxyphenylalanine (DOPA) and through the four of Non-aqueous processing
Hydrogen furan 20mL, adds the 10mL tetrahydrofuran solution dissolved with 0.5g (1.69mmol) triphosgene in constant pressure funnel.Rise
Triphosgene solution in constant pressure funnel, to about 50 DEG C, is slowly added in three-neck flask by temperature under magnetic stirring.Instead
30min should be reacted again after becoming light yellow transparent solution to solution.At this moment lead to nitrogen remaining phosgene and HCl gas to be brought into
In absorption plant containing saturated NaOH solution.After tail gas absorption processes, concentration of reaction solution, add appropriate normal hexane.
Standing, have pale yellow oil to separate out, several times, gained pale yellow oil is L-3,4-dihydroxy benzenes methyl ammonia to repeated precipitation
Guanidine-acetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA).
HP(DOPA-Glu-EG2) preparation: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen
50 mL three-neck flasks of protection device add 1.65 g(6.00mmol) Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl
Base inner-acid anhydride (Glu-EG2-NCA) and through oxolane 10 mL, addition 3mL in constant pressure funnel of Non-aqueous processing
Initiator hyperbranched polyglycidyl ether 0.05 g(0.0192mmol that anhydrous tetrahydro furan dissolves), it is slowly added into three necks and burns
In Ping, react 72h, obtain faint yellow sticky mass.Add in constant pressure funnel again and dissolve with 10mL anhydrous tetrahydro furan
L-3,4-dihydroxy benzenes methyl aminoacetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA) 1.34 g(6.00mmol), be slowly added to
In three-neck flask, react 72h, obtain faint yellow sticky mass and be crude product.Add dehydrated alcohol in the crude product, produce
Pale yellow precipitate, the pale yellow oil of gained is HP (DOPA-Glu-EG2)。
By the Thermo-sensitive of polymer and the detection of bond performance being found its response temperature, at 37 ± 0.5 DEG C, is cohered strong
Degree is about at about 90 Kpa.
Embodiment 2:HP (Arg-DOPA-Glu-EG2) prepare
Glu-EG2Preparation: with embodiment 1；
Glu-EG2The preparation of-NCA: with embodiment 1；
The preparation of DOPA-NCA: with embodiment 1；
HP(DOPA-Glu-EG2) preparation: with embodiment 1；
The preparation of Arg-NCA: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection device
100mL three-neck flask adds benzyloxycarbonyl group arginine 6.6g(21.43mmol) and solvents tetrahydrofurane 30mL.Drip in constant voltage
In liquid funnel add 5mL contain 1mL phosphorus tribromide (10.64mmol)) tetrahydrofuran solution.Nitrogen is protected, and drips under ice bath
In three-neck flask, then room temperature reaction 16h.Reaction terminates the layering of rear reactant liquor, is toppled over by the oxolane liquid on reaction upper strata
Out, layer oily matter is with substantial amounts of oxolane cyclic washing, and obtaining water white transparency oily thing is acid in arginine-N-carbonyl
Acid anhydride (Arg-NCA).
HP(Arg-DOPA-Glu-EG2) preparation: in constant pressure funnel, addition 10mL anhydrous tetrahydro furan is molten
Arginine-N-carbonyl inner-acid anhydride (Arg-NCA) 0.76 g(3.80mmol solved), it is slowly added into stepThree-neck flask
In, react three days, obtain faint yellow sticky mass and be crude product.Crude product absolute ethanol washing, the faint yellow oily of gained
Thing is HP (Arg-DOPA-Glu-EG2)。
By the Thermo-sensitive of polymer and the detection of bond performance being found its response temperature, at 37 ± 0.5 DEG C, is cohered strong
Degree is about at about 100 Kpa.
Embodiment 3:HP (Cys-Arg-DOPA-Glu-EG2) preparation
Glu-EG2Preparation: with embodiment 1；
Glu-EG2The preparation of-NCA: with embodiment 1；
The preparation of DOPA-NCA: with embodiment 1；
HP(DOPA-Glu-EG2) preparation: with embodiment 1；
The preparation of Arg-NCA: with embodiment 2；
HP(Arg-DOPA-Glu-EG2) preparation: with embodiment 2；
The preparation of Cys-NCA: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection device
Adding 1 g (8.25mmol) cysteine and the oxolane 30mL through Non-aqueous processing in 100mL three-neck flask, constant voltage is dripped
Liquid funnel adds the 10mL tetrahydrofuran solution dissolved with 1.47 g (4.96mmol) triphosgene.It is warming up to about 50 DEG C, at magnetic
Under power stirring, the triphosgene solution in constant pressure funnel is slowly added in three-neck flask.Reaction becomes faint yellow to solution
30min is reacted again after clear solution.At this moment lead to nitrogen to be brought into remaining phosgene and HCl gas containing saturated NaOH solution
In absorption plant.After tail gas absorption processes, concentration of reaction solution, add appropriate normal hexane.Stand, have faint yellow solid to analyse
Go out, be filtrated to get crude product.Crude product normal hexane and re-crystallizing in ethyl acetate, obtain white crystal i.e. cysteine-N-carbonyl
Base inner-acid anhydride (Cys-NCA).
HP(Cys-Arg-DOPA-Glu-EG2) preparation: addition 10mL anhydrous tetrahydrochysene furan in constant pressure funnel
Mutter dissolve cysteine-N-carbonyl inner-acid anhydride (Cys-NCA) 0.56 g (3.80mol), be slowly added into stepThree
In neck flask, react three days, obtain faint yellow sticky mass and be crude product.Crude product absolute ethanol washing, obtains faint yellow
Grease is HP (Cys-Arg-DOPA-Glu-EG2)。
By the Thermo-sensitive of polymer and the detection of bond performance being found its response temperature, at 37 ± 0.5 DEG C, is cohered strong
Degree is about at about 108Kpa.
Embodiment 4:HP (AM-Lys-Arg-DOPA-Glu-EG2) preparation:
Glu-EG2Preparation: with embodiment 1；
Glu-EG2The preparation of-NCA: with embodiment 1；
The preparation of DOPA-NCA: with embodiment 1；
HP(DOPA-Glu-EG2) preparation: with embodiment 1；
The preparation of Arg-NCA: with embodiment 2；
HP(Arg-DOPA-Glu-EG2) preparation: with embodiment 2；
The preparation of AM-Lys-NCA:
Acrylamide lysine mantoquita: equipped with magnetic stirring apparatus, thermometer device 50mL round-bottomed flask in add 1 g
(5.47mmol) lysine hydrochloride is simultaneously introduced 12 mL water, refluxes, by 0.66 g (2.99 mmol) alkali formula carbon at 90 DEG C
Acid copper is slowly added in the solution of lysine hydrochloride, stirs 10 min, then cools down, and filters insoluble residue,
In filtrate, add 5.8 mL acetone, be subsequently adding the potassium hydroxide solution of 2.74 mL 2 mol/L, this mixed solution is added to
Equipped with in the 100mL three-neck flask of magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection device, two constant voltages
Dropping funnel is separately added into 0.552 mL (6.79mmol) acryloyl chloride and the potassium hydroxide solution of 3.08 mL 2 mol/L,
It is slowly dropped in reaction system under ice bath, reacts 12 h, filter the copper complex formazan precipitate of acrylamide lysine, successively
With water, methanol, ether washs.Obtained blue solid is acrylamide copper lysine complex.
The preparation of acrylamide lysine: by acrylamide copper lysine complex 0.21 g obtained by upper step
(0.43mmol) join equipped with magnetic stirring apparatus, thermometer, nitrogen protection device 100mL round-bottomed flask in, be simultaneously introduced 3
ML water and 3 mL, dissolved with the chloroformic solution of 0.079 g (0.54mmol) 8-hydroxyquinoline, are stirred at room temperature about 12 h, just have
Green precipitate occurs at chloroform layer, is filtered to remove precipitation, filtrate be transferred in separatory funnel, removes chloroform layer,
Wash 3-4 time with chloroform again, remaining water layer is concentrated into white solid, then with oxolane and water recrystallization, obtain
White crystal is acrylamide lysine, and productivity is 45%.
The preparation of AM-Lys-NCA: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection device
100mL three-neck flask adds the acrylamide lysine obtained by the upper step of 2 g (10.00mmol) and through Non-aqueous processing
Oxolane 40mL, is simultaneously introduced hydroquinone of polymerization retarder 0.011g (0.1mmol), adds 20mL molten in constant pressure funnel
Have 1.78 g(5.99mmol) tetrahydrofuran solution of triphosgene.It is warming up to about 50 DEG C, under magnetic stirring by constant pressure addition
Triphosgene solution in funnel is slowly added in three-neck flask.Reaction is reacted after becoming light yellow transparent solution to solution again
30min.At this moment lead to nitrogen remaining phosgene and HCl gas to be brought in the absorption plant containing saturated NaOH solution.Pass through
After tail gas absorption processes, concentration of reaction solution, add appropriate normal hexane.Stand, have faint yellow solid to separate out, be filtrated to get thick product
Thing.Crude product normal hexane and re-crystallizing in ethyl acetate, obtain acid in white crystal i.e. ε-N acrylamide lysine-N-carbonyl
Acid anhydride (AM-Lys-NCA), yield 60%.
HP(AM-Lys-Arg-DOPA-Glu-EG2) preparation: addition 10mL anhydrous four in constant pressure funnel
ε-N acrylamide lysine-N-carbonyl inner-acid anhydride (AM-Lys-NCA) 0.86 g (3.84mmol) that hydrogen furan dissolves is slow
Slowly step is joinedThree-neck flask in, react three days, obtain faint yellow sticky mass and be crude product, crude product is with anhydrous
Washing with alcohol, obtains pale yellow oil and is HP (AM-Lys-Arg-DOPA-Glu-EG2).Its structural formula is as follows:
By the Thermo-sensitive of polymer and the detection of bond performance are found its response temperature at 37 ± 0.5 DEG C, bond strength is about
At about 117Kpa.
Embodiment 5:PAMAM (DOPA-Glu-EG2) preparation
Glu-EG2Preparation: with embodiment 1；
The preparation of Glu-EG2-NCA: with embodiment 1；
The preparation of DOPA-NCA: with embodiment 1；
PAMAM(DOPA-Glu-EG2) preparation: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protect
50 mL three-neck flasks of protection unit add 0.62 g(2.25mmol) Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl
Inner-acid anhydride (Glu-EG2-NCA) and through oxolane 10 mL of Non-aqueous processing, in constant pressure funnel addition 3mL without
Initiator ultrabranching polyamide-amine 0.05 g(0.0072mmol that water oxolane dissolves), it is slowly added in three-neck flask,
React three days, obtain faint yellow sticky mass.The L-dissolved with 10mL anhydrous tetrahydro furan is added again in constant pressure funnel
3,4-dihydroxy benzenes methyl aminoacetic acid-N-carbonyl inner-acid anhydride (DOPA-NCA) 0.51 g(2.25mmol), it is slowly added into three
In neck flask, react three days, obtain faint yellow sticky mass and be crude product.Add dehydrated alcohol in the crude product, produce light
Yellow mercury oxide, the pale yellow oil of gained is PAMAM (DOPA-Glu-EG2).By to the Thermo-sensitive of polymer and cohering
The detection of performance find its response temperature at 37 ± 0.5 DEG C, bond strength is about at about 93 Kpa.
Embodiment 6:PAMAM (Arg-DOPA-Glu-EG2) prepare
Glu-EG2Preparation: with embodiment 1；
The preparation of Glu-EG2-NCA: with embodiment 1；
The preparation of DOPA-NCA: with embodiment 1；
PAMAM(DOPA-Glu-EG2) preparation: with embodiment 5；
The preparation of Arg-NCA: with embodiment 2；
PAMAM(Arg-DOPA-Glu-EG2) preparation: in constant pressure funnel, addition 10mL anhydrous tetrahydro furan is molten
Arginine-N-carbonyl inner-acid anhydride (Arg-NCA) 0.29 g(1.44mmol solved), it is slowly added into stepThree-neck flask
In, react three days, obtain faint yellow sticky mass and be crude product.Crude product absolute ethanol washing, the faint yellow oily of gained
Thing is PAMAM (Arg-DOPA-Glu-EG2)。
By the Thermo-sensitive of polymer and the detection of bond performance being found its response temperature, at about 37 ± 0.5 DEG C, sticks
Knotting strength is about at about 102 Kpa.
Embodiment 7:PAMAM (Cys-Arg-DOPA-Glu-EG2) preparation
Glu-EG2Preparation: with embodiment 1；
Glu-EG2The preparation of-NCA: with embodiment 1；
The preparation of DOPA-NCA: with embodiment 1；
PAMAM(DOPA-Glu-EG2) preparation: with embodiment 5；
The preparation of Arg-NCA: with embodiment 2；
PAMAM(Arg-DOPA-Glu-EG2) preparation: with embodiment 6；
The preparation of Cys-NCA: equipped with magnetic stirring apparatus, thermometer, constant pressure funnel and nitrogen protection device
Adding 1 g (8.25mmol) cysteine and the oxolane 30mL through Non-aqueous processing in 100mL three-neck flask, constant voltage is dripped
Liquid funnel adds the 10mL tetrahydrofuran solution dissolved with 1.47 g (4.96mmol) triphosgene.It is warming up to about 50 DEG C, at magnetic
Under power stirring, the triphosgene solution in constant pressure funnel is slowly added in three-neck flask.Reaction becomes faint yellow to solution
30min is reacted again after clear solution.At this moment lead to nitrogen to be brought into remaining phosgene and HCl gas containing saturated NaOH solution
In absorption plant.After tail gas absorption processes, concentration of reaction solution, add appropriate normal hexane.Stand, have faint yellow solid to analyse
Go out, be filtrated to get crude product.Crude product normal hexane and re-crystallizing in ethyl acetate, obtain white crystal i.e. cysteine-N-carbonyl
Base inner-acid anhydride (Cys-NCA).
PAMAM (Cys-Arg-DOPA-Glu-EG2) preparation: addition 10mL anhydrous four in constant pressure funnel
The cysteine-N-carbonyl inner-acid anhydride (Cys-NCA) 0.22g (1.44mmol) that hydrogen furan dissolves, is slowly added into step
Three-neck flask in, react three days, obtain faint yellow sticky mass and be crude product.Crude product absolute ethanol washing, obtains light
Yellow oil is PAMAM (Cys-Arg-DOPA-Glu-EG2)。
By the Thermo-sensitive of polymer and the detection of bond performance being found its response temperature, at 37 ± 0.5 DEG C, is cohered strong
Degree is about at about 110Kpa.
Embodiment 8:PAMAM (AM-Lys-Arg-DOPA-Glu-EG2) preparation:
Glu-EG2Preparation: with embodiment 1；
Glu-EG2The preparation of-NCA: with embodiment 1；
The preparation of DOPA-NCA: with embodiment 1；
PAMAM(DOPA-Glu-EG2) preparation: with embodiment 5；
The preparation of Arg-NCA: with embodiment 2；
PAMAM(Arg-DOPA-Glu-EG2) preparation: with embodiment 6；
The preparation of AM-Lys-NCA: with embodiment 4；
PAMAM(AM-Lys-Arg-DOPA-Glu-EG2) preparation: the anhydrous tetrahydrochysene of addition 10mL in constant pressure funnel
ε-N acrylamide lysine-N-carbonyl inner-acid anhydride (AM-Lys-NCA) 0.33 g (1.44mmol) that furan dissolves, slowly
Join stepThree-neck flask in, react three days, obtain faint yellow sticky mass and be crude product, the anhydrous second of crude product
Alcohol washs, and obtains pale yellow oil and is PAMAM (AM-Lys-Arg-DOPA-Glu-EG2)。
By the Thermo-sensitive of polymer and the detection of bond performance being found its response temperature, at 37 ± 0.5 DEG C, is cohered strong
Degree is about at about 120Kpa.
Claims (10)
1. a preparation method for temperature response type macromolecule bio-medical adhesive, is with polyhydroxy or polyamino hyperbranched poly
Compound is initiator, with oxolane as solvent, has the aminoacid of N-carbonyl inner-acid anhydride as function monomer with end, and nitrogen is protected
Protecting, react 48 ~ 72h in polymerized at room temperature, after reaction terminates, the mixed solution of crude product triethylamine-ethanol precipitates and obtains.
2. the preparation method of temperature response type macromolecule bio-medical adhesive as claimed in claim 1, it is characterised in that: described
End has the aminoacid of N-carbonyl inner-acid anhydride to be Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride, L-3,4-bis-
Hydroxyphenylmethyl glycine-N-carbonyl inner-acid anhydride, arginine-N-carbonyl inner-acid anhydride, cysteine-N-carbonyl inner-acid anhydride or ε-
At least two in N acrylamide lysine-N-carbonyl inner-acid anhydride.
3. the preparation method of temperature response type macromolecule bio-medical adhesive as claimed in claim 1, it is characterised in that: described
Polyhydroxy dissaving polymer is to react with BDO and metallic potassium to cause epoxy prapanol open loop, obtains hyperbranched poly and shrinks
Glycerin ether, adds metallic potassium, the hyperbranched polyhydroxylated polymer potassium alcoholate that reaction obtains.
The preparation method of a kind of temperature response type macromolecule bio-medical adhesive the most as claimed in claim 1, it is characterised in that:
Described polyamino dissaving polymer is ultrabranching polyamide-amine.
5. the preparation method of any temperature response type macromolecule bio-medical adhesive as described in claim 1-4, it is special
Levy and be: described initiator is 1:620 ~ 1:1030 with the mole of function monomer.
6. the preparation method of any temperature response type macromolecule bio-medical adhesive as described in claim 1-4, it is special
Levy and be: described function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride, L-3,4-dihydroxy benzenes
During methyl aminoacetic acid-N-carbonyl inner-acid anhydride, the mol ratio of the two is 1:0.9 ~ 1:1.1.
7. the preparation method of any temperature response type macromolecule bio-medical adhesive as described in claim 1-4, it is special
Levy and be: described function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride, L-3,4-dihydroxy benzenes
When methyl aminoacetic acid-N-carbonyl inner-acid anhydride, arginine-N-carbonyl inner-acid anhydride, the mol ratio of three is 1:0.9:0.58 ~ 1:
1.1:0.63。
8. the preparation method of any temperature response type macromolecule bio-medical adhesive as described in claim 1-4, it is special
Levy and be: function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride, L-3,4-dihydroxy benzenes methyl
When glycine-N-carbonyl inner-acid anhydride, arginine-N-carbonyl inner-acid anhydride, cysteine-N-carbonyl inner-acid anhydride, four mole
Ratio is 1:0.9:0.58:0.58 ~ 1:1.1:0.63:0.63.
9. the preparation method of any one temperature response type macromolecule bio-medical adhesive as described in claim 1-4, it is special
Levy and be: function monomer is Pidolidone-β-diethylene glycol monomethyl ether ester-N-carbonyl inner-acid anhydride, L-3,4-dihydroxy benzenes methyl
When glycine-N-carbonyl inner-acid anhydride, arginine-N-carbonyl inner-acid anhydride, ε-N acrylamide lysine-N-carbonyl inner-acid anhydride,
The mol ratio of four is 1:0.9:0.58:0.58 ~ 1:1.1:0.63:0.64.
10. the temperature response type macromolecule bio-medical adhesive that as claimed in claim 1 prepared by method, it is characterised in that: temperature
Degree response is when 37 ± 0.5 DEG C, and bond strength is between 90 ~ 130 Kpa.
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| CN109925540A (en) * | 2019-03-14 | 2019-06-25 | 西南交通大学 | Albumin is mediated to form method, biomaterial and its application of albumin layer on the surface of the material |
| CN110452374A (en) * | 2019-08-30 | 2019-11-15 | 苏州大学 | Poly- polypeptide of three-dimensional spherical shape α spiral cation with efficient gene delivery ability and the preparation method and application thereof |
| CN110832006A (en) * | 2017-04-28 | 2020-02-21 | 赢创德固赛有限公司 | Biodegradable bone glue |
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| CN110832006A (en) * | 2017-04-28 | 2020-02-21 | 赢创德固赛有限公司 | Biodegradable bone glue |
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