CN104623725B - Bioadhesive and preparation method thereof - Google Patents
Bioadhesive and preparation method thereof Download PDFInfo
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- CN104623725B CN104623725B CN201410852796.3A CN201410852796A CN104623725B CN 104623725 B CN104623725 B CN 104623725B CN 201410852796 A CN201410852796 A CN 201410852796A CN 104623725 B CN104623725 B CN 104623725B
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Abstract
The invention discloses a bioadhesive, which contains a polymer and a solvent, wherein the polymer is a graft of dopamine or mussel adhesive protein and oxidized graft A; the graft A is a graft of a macromolecular substance andan acrylate compound; a six-membered ring in a macromolecular substance in the oxidized graft A is bonded with an aldehyde group; the macromolecular substance is selected from at least one of hyaluronic acid, chondroitin sulfate, gelatin, polypeptide, alginic acid and chitosan; and the acrylate compound is selected from one of methyl methacrylate, methacrylate, glycidyl methacrylate and acrylic ester. The invention further provides a preparation method of the bioadhesive. The bioadhesive has the advantages of being good in biological activity, relatively good in mechanical property and biodegradable, and is capable of promoting tissue healing in a moist environment.
Description
Technical field
The present invention relates to a kind of biological adhesive and preparation method thereof, this binding agent be used for moist environment tissue bonding and
Repair, be particularly well-suited to bonding and the reparation in cartilaginous tissue field.
Background technology
It is complexity and the wound to patient reducing operation in recent decades, medical adhesive obtains and develops rapidly
Apply with extensive.In surgical operation, medical adhesive is used for some organs and the local bond organized and repairing, and Post operation stitches
The prevention of blood capillary oozing of blood at conjunction, gynecological is used for viscous stifled fallopian tube and completes to ligature, and gear division is used for the repairing of tooth, in bone surgery
Skeleton, the combination in joint and positioning.Clinically mainly being integrated with stitching thread or tissue adhesive at present needs the soft of combination
Tissue.Due to tissue adhesive can effectively reduce operative complications and reduce process again, just progressively obtain the green grass or young crops of clinician
Look at.There are α-cyanoacrylate analog derivative, glutaraldehyde-albumin analog derivative and fibre in the tissue adhesive clinically using at present
Fibrillarin glue.But these medical adhesives still suffer from various defects.As a-cyanoacrylate class although the bonding time is short,
But glue-line fragility is big, unavoidably produces formaldehyde during decomposition；Tooth adhesive is easily subject to temperature, intensity, physiological environment factor shadow
Ring and be easily caused cementation loosely etc..
The repair process of cartilage is the bone below formation and defect surrounding normal cartilage, defect by fibrin clot
The cascade reaction of the chondroblast in marrow or synovial tissue source, is finally completed the tissue repair of defect.Traditional cartilage
The technology repaired, such as under cartilage, boring, cleaning Drilling or micro fractures, are all using the tissue having blood supply under cartilage and bone
Marrow, and use in conjunction removes the operation such as cartilage fragment to promote repair of cartilage.But these methods can lead to fibrocartilaginous shape
Become, its composition, structure and mechanical property are different from normal cartilage.Can be used for after cartilage injury currently without any adhesive product
Bonding.
Content of the invention
In view of this it is necessary to provide a kind of biological adhesive and preparation method thereof, this bio-adhesive properties is excellent, energy
Effectively overcome the defect of above-mentioned binding agent.
A kind of biological adhesive, it contains polymer and solvent, and this polymer is dopamine or makes a gift of sufficient attachment proteinses and oxygen
The graft of the graft a after change, wherein this graft a are the graft of polymer substance and acrylic ester compound；Should
It is connected with aldehyde radical on hexatomic ring in the polymer substance in graft a after oxidation；This polymer substance is selected from hyaluronic acid, sulphuric acid
At least one in chrondroitin, gelatin, polypeptide, alginic acid and shitosan；This acrylic ester compound is selected from methacrylic acid
One of methyl ester, methacrylate, glycidyl methacrylate and acrylate.
Further, described solvent is one of water, the aqueous solution of sodium chloride, phosphate buffered solution.
Further, in this biological adhesive, the mass percentage concentration of polymer is 10% ~ 85%.
Further, described aldehyde radical is formed via the adjacent hydroxyl oxidize on hexatomic ring in polymer substance.
A kind of preparation method of biological adhesive, it comprises the steps:
Prepare graft a, this graft a is the graft of polymer substance and acrylic ester compound, wherein this height
Molecular substance is selected from least one in hyaluronic acid, chondroitin sulfate, gelatin, polypeptide, alginic acid and shitosan；This propylene
Acid esters compound is selected from methyl methacrylate, methacrylate, glycidyl methacrylate and acrylate
One kind；
Aoxidize described graft a, make the adjacent hydroxyl oxidize on hexatomic ring in the polymer substance in graft a be aldehyde radical；
Prepare polymer, this polymer is dopamine or the graft making a gift of the graft a after sufficient attachment proteinses and oxidation；
Described polymer is dissolved in solvent, described biological adhesive is obtained.
Further, the step that this prepares graft a includes: dissolves described polymer substance using solvent m；Add propylene
Acid esters compound is reacted, and the molal quantity of the wherein acrylic ester compound of addition is polymer substance molal quantity
10-50 times；Organic solvent n is added to be precipitated, the precipitate obtaining is graft a.
Further, this solvent m be water or water with organic solvent, inorganic salt, organic acid three in the mixing of any one
Thing, this organic solvent n is acetone or ethanol.
Further, mass-volume concentration in solvent m for this hyaluronic acid is 0.001 ~ 0.1g/ml；Chondroitin sulfate
Mass-volume concentration in solvent m is 0.001 ~ 0.2g/ml；Mass-volume concentration in solvent m for the gelatin be 0.001 ~
0.25g/ml, mass-volume concentration in solvent m for the alginic acid is 0.005 ~ 0.1g/ml, mass body in solvent m for the shitosan
Long-pending concentration is 0.001 ~ 0.1g/ml.
Further, the step aoxidizing described graft a includes: described graft a is dissolved in the water, adds oxidant
Reacted, this oxidant is one of sodium metaperiodate, hydrogen peroxide, sodium hypochlorite；Graft a after oxidation is carried out separating
Purification, drying.
Further, aoxidize in the solution of oxidation reaction in the step of described graft a, the percent mass of graft a is dense
Spend for 0.1% ~ 10%, when oxidant uses sodium metaperiodate, the mass percentage concentration of sodium metaperiodate is 1% ~ 20%；When oxidant uses
Hydrogen peroxide, the mass percentage concentration of hydrogen peroxide is 0.5% ~ 15%；When oxidant uses sodium hypochlorite, the percent mass of sodium hypochlorite
Concentration is 0.5% ~ 20%.
Further, the described step preparing polymer includes: the graft a after described oxidation is dissolved in the water, plus
Enter carbodiimides and reactant liquor is obtained, control the ph value of reactant liquor for 4 ~ 6 and add dopamine or make a gift of foot under the protection of nitrogen
Attachment proteinses carry out reaction and obtain polymer；Prepared polymer carried out isolate and purify, be dried.
Further, the mass percentage concentration after the graft a after described oxidation is dissolved in water is 0.1% ~ 10%, carbonization two
The mass percentage concentration of imines is 0.5 ~ 5 times of graft a mass percentage concentration after oxidation, dopamine or make a gift of sufficient attachment proteinses
Mass percentage concentration be 0.1% ~ 20%.
Further, the method also includes described polymer is dissolved in after solvent and is irradiated uviol lamp and makes crosslinked polymer
Step.
The biological adhesive of the present invention has good biological activity, preferable mechanical property, and biodegradable, promotion is wet
The advantages of profit environmental organization heals.This biological adhesive is applied to the moistening tissue of bonding, particularly cartilaginous tissue reparation and defect
The reparation (reparation of osseous tissue and dental tissue) of tissue, has broad application prospects.
Brief description
Fig. 1 is the composition principle schematic diagram of the biological adhesive of present pre-ferred embodiments.
Specific embodiment
Refer to Fig. 1, the preparation method of the biological adhesive of present pre-ferred embodiments, it comprises the following steps:
(1) prepare graft a, this graft a is the graft of polymer substance and acrylic ester compound.
This polymer substance is natural polymer substance, be chosen in particular from hyaluronic acid, chondroitin sulfate, gelatin, polypeptide,
At least one in alginic acid and shitosan.This acrylic ester compound is selected from methyl methacrylate, methacrylic acid
One of ester, glycidyl methacrylate and acrylate.
This step (1), particularly as follows: dissolving described polymer substance using solvent m, is subsequently added into acrylic ester compound
Reacted, the molal quantity of the wherein acrylic ester compound of addition is 10 ~ 50 times of polymer substance molal quantity, Ran Houjia
Enter organic solvent n to be precipitated, the precipitate obtaining as graft a(polymer substance is connect with acrylic ester compound
Branch thing).
This step (1) also includes the precipitate obtaining adds water and is dissolved, then is vacuum dried described sedimentary step.
In the present embodiment, the volume of the organic solvent n of addition is 20-40 times of solvent m volume.
In described step (1), this organic solvent n is acetone or ethanol, and this solvent m can be water or water and organic solvent, no
The mixture of any one in machine salt, organic acid three.The different polymer substance of correspondence, solvent m species can be different, such as when height
When molecular substance is hyaluronic acid and/or alginic acid, solvent m is phosphate buffer (ph=3)；As being sulfur when polymer substance
During aching and limp ossein, solvent m is the aqueous solution (volume ratio as acetone and water is 1:1) of acetone；As being gelatin when polymer substance
When, solvent m is the aqueous solution (volume ratio as acetone and water is 1:1) of acetone；As being shitosan when polymer substance, solvent m
For vinegar aqueous acid (as concentration is 0.02 ~ 0.5 mole every liter).
In addition, when described solvent m selects the aqueous solution of acetone, adding acrylic ester compound in this step (1)
Also need to add triethylamine (catalyst), wherein acrylic ester compound and the volume ratio of triethylamine are 1:1 ~ 1:5 simultaneously.This is saturating
The molecular weight of bright matter acid is 104~106Da, the molecular weight of this chondroitin sulfate is 104~105da.
The different polymer substance of correspondence, concentration in solvent m for the polymer substance is different, and such as hyaluronic acid is in solvent m
In mass-volume concentration be 0.001 ~ 0.1g/ml；Chondroitin sulfate mass-volume concentration in solvent m is 0.001 ~ 0.20g/
ml；Mass-volume concentration in solvent m for the gelatin is 0.001 ~ 0.25g/ml, mass-volume concentration in solvent m for the alginic acid
For 0.005 ~ 0.1g/ml, mass-volume concentration in solvent m for the shitosan is 0.001 ~ 0.10g/ml.
(2) aoxidize described graft a, make the hydroxyl oxidize on hexatomic ring in the polymer substance in graft a be aldehyde radical.
Particularly as follows: described graft a is dissolved in the water, add oxidant to carry out reaction makes polymer to this step (2)
Adjacent hydroxyl oxidize on hexatomic ring in matter is aldehyde radical.This oxidant is one of sodium metaperiodate, hydrogen peroxide, sodium hypochlorite.
In the solution of oxidation reaction, the mass percentage concentration of described graft a is 0.1% ~ 10%, corresponds to using different oxygen
During agent, the concentration of oxidant is different, and the mass percentage concentration of such as sodium metaperiodate is 1% ~ 20%, the mass percentage concentration of hydrogen peroxide
For 0.5% ~ 15%, the mass percentage concentration of sodium hypochlorite is 0.5% ~ 20%.
Oxidation reaction rear for a period of time (being 0.1 ~ 24 hour in the present embodiment), can add terminator (as ethylene glycol) with end
Oxidation is reacted, and then the graft a after oxidation is carried out with the step isolating and purifying, being dried.
This step isolates and purifies concretely in (2): is carried out using the bag filter that molecular cut off is 1000 ~ 8000
Analysis.Need in the present embodiment to dialyse three days, change three water every day.It is dried concretely in this step: by the solution through dialysis
Put into cryogenic refrigerator and carry out pre-cooling (- 20 DEG C to -80 DEG C can be cooled in advance), then lyophilization.
(3) prepare polymer, this polymer is dopamine or the grafting making a gift of the graft a after sufficient attachment proteinses and oxidation
Thing.
This step (3) particularly as follows: by described oxidation after graft a be dissolved in the water, add carbodiimides (edc) and
N- N-Hydroxysuccinimide (nhs), obtains reactant liquor.Then add dopamine under the protection of nitrogen or make a gift of sufficient attachment proteinses and enter
Row reaction, the graft obtaining dopamine or making a gift of the graft a after sufficient attachment proteinses and described oxidation, i.e. polymer, then right
Prepared polymer carries out the step isolating and purifying, being dried.Wherein, nhs may be selected add or without.
Wherein, edc and nhs is activator, activating dopamine or make a gift of carboxyl on sufficient attachment proteinses, more favourable dopamine or
The carrying out that graft a after making a gift of sufficient attachment proteinses and aoxidizing reacts.
In described polymer, dopamine or make a gift of sufficient attachment proteinses and will graft on polymer substance, as shown in Figure 1.
Mass percentage concentration after graft a after oxidation in described step (3) is dissolved in water is 0.1% ~ 10%, carbonization two
The mass percentage concentration of imines is 0.5 ~ 5 times of the mass percentage concentration of graft a after oxidation, n- N-Hydroxysuccinimide
Mass percentage concentration is 1 ~ 10 times of carbodiimides mass percentage concentration, dopamine or make a gift of sufficient attachment proteinses percent mass dense
Spend for 0.1% ~ 20%.
In addition, adding dopamine or before making a gift of sufficient attachment proteinses in step (3), also include reactant liquor is carried out ph adjust to
4.0 ~ 6.0 step, is carried out under sour environment with ensureing to react.Ph adjustment can be by adding sodium hydroxide solution to reactant liquor
Middle realization.
Described make a gift of sufficient attachment proteinses be make a gift of sufficient attachment proteinses 3, make a gift of one of sufficient attachment proteinses 5 or two kinds.
In this step, purification procedures are concretely: carried out using the bag filter that molecular cut off is 1000 ~ 8000
Analysis.Need in the present embodiment to dialyse three days, first day every 4 hour changes a water, change three water (etc. within second day and the 3rd day one day
Interval).It is dried in this step concretely: the solution through dialysis is put into cryogenic refrigerator and carried out pre-cooling (- 20 DEG C can be cooled in advance
To -80 DEG C), then lyophilization, obtain faint yellow spongy solid, as described polymer.
(4) described polymer is dissolved in solvent, irradiating uviol lamp makes crosslinked polymer, that is, described bioadhesive is obtained
Agent.
Described solvent can be one of water, the aqueous solution of sodium chloride, phosphate buffered solution.This biological adhesive dense
Spend for 10% ~ 85%, can be adjusted as needed.
The wavelength of uviol lamp is 200-400nm, and the time of irradiation is 10s ~ 3600s.
It should be understood that described irradiation uviol lamp makes the step of crosslinked polymer can also omit.
On address the water being mentioned below and refer both to deionized water.
The biological adhesive of the present invention, it contains polymer, and this polymer is dopamine or makes a gift of sufficient attachment proteinses and oxidation
The graft of graft a afterwards, wherein this graft a are the graft of polymer substance and acrylic ester compound, this oxygen
Graft a after change be by the hydroxyl oxidize on hexatomic ring in the polymer substance in graft a be aldehyde radical.This polymer substance
At least one in hyaluronic acid, chondroitin sulfate, gelatin, polypeptide, alginic acid and shitosan.This esters of acrylic acid
Compound is selected from one of methyl methacrylate, methacrylate, glycidyl methacrylate and acrylate.
The biological adhesive of the present invention, it contains solvent further, and described solvent can be water, the aqueous solution of sodium chloride, phosphorus
One of hydrochlorate buffer solution.The concentration of this biological adhesive is 10% ~ 85%.
The biological adhesive of the present invention has the advantage that the addition of (1) small molecule acrylic ester compound improves
The mechanical property of polymer substance；(2) by the adjacent hydroxyl oxidize on hexatomic ring in natural polymer be aldehyde radical, aldehyde radical with tissue in
Amino occur " schiff bases " reaction, thus built a binding agent with tissue combine bridge；(3) dopamine or to make a gift of foot viscous
The addition of attached albumen improves the adhesion strength of binding agent；(4) ultra violet lamp cross-linked binder, nontoxic, improve viscous further
The mechanical property of mixture.
The biological adhesive of the present invention has good biological activity, preferable mechanical property, biodegradable, promotion group
The advantages of knit healing.The biological adhesive degradation in vivo of the present invention or the time being fully absorbed by body are 1 ~ 8 month.According to
Tissue adhesive's adhesive property test method (yy/t 0729.3) is tested, and stretching under hygrometric state for this biological adhesive is strong
Spend for 5 ~ 120mpa.It is 0-1 level using national standard test cell toxicity.
This biological adhesive is applied to adhesion organization, the particularly reparation (osseous tissue of cartilaginous tissue reparation and defective tissue
Reparation with dental tissue), have broad application prospects.
The present invention is specifically described below by embodiment.
Embodiment 1
Step (1): prepare graft a(hyaluronic acid grafted methacrylic acid methyl ester).
By 1g hyaluronic acid, (molecular weight is 1.6 × 106) add to 100ml phosphate buffered solution (ph=3), machinery
Stirring and dissolving 24h, rotating speed is 280 revs/min (rpm)；Then add 2.2ml methyl methacrylate wherein, continue stirring
Reaction 5 days；Add acetone to be precipitated, and remove unreacted methyl methacrylate and other small molecules, wherein acetone
Addition volume be 20 times of phosphate buffered solution volume；Dissolved with water after being precipitated thing, add acetone and sink
Form sediment, be repeated twice；Finally carry out being vacuum dried 48h in room temperature, vacuum is -100kpa, obtains final product graft a(hyaluronic acid and connects
Branch methyl methacrylate, is named as hyaluronic acid acrylate ester).
Step (2): aoxidize described graft a.
Weigh 0.3g graft a, be added into 5ml aqueous solution, wait to be completely dissolved, add 0.308g sodium metaperiodate,
Magnetic agitation lucifuge reacts 6h, and the speed of magnetic agitation is 480rpm；Then dialyse 3 days, the molecular cut off of bag filter is
8000-14000；Last lyophilization 3 days, obtains the hyaluronic acid acrylate ester aldehyde of white sponge.
Step (3): prepare polymer, the grafting of the graft a after dopamine and oxidation.
Weigh 1g hyaluronic acid acrylate ester aldehyde, be added in 100ml round bottom there-necked flask, be subsequently adding 40ml water-soluble
Liquid, treats that it is completely dissolved, and sequentially adds 0.955g carbodiimides, 1.15g n- N-Hydroxysuccinimide, magnetic agitation dissolves,
With the sodium hydroxide of 0.1mol/l, ph is adjusted to 5.5；It is passed through nitrogen 15min after all dissolving, then evacuation 15min, then
It is passed through nitrogen 15min, then evacuation 15min again, be subsequently adding 0.8g dopamine, evacuation 15min, be passed through nitrogen in nitrogen
Protection under react 24h, question response terminated to dialyse three days, changed within first day a water every 3 hours, and beginning in second day changes three in one day
Secondary water, the molecular cut off of bag filter is 7000；Last lyophilization three days, obtains (the name of faint yellow spongiform polymer
For hyaluronic acid acrylate ester aldehyde-dopamine).
Step (4): described polymer is dissolved in solvent, irradiating uviol lamp makes crosslinked polymer, that is, described biology is obtained
Binding agent.
Weigh the polymer (hyaluronic acid acrylate ester aldehyde-dopamine) of certain mass, be dissolved in water, configuration concentration
Solution for 30%, waits to be completely dissolved, and after obtaining the solution of stable homogeneous, uses ultra violet lamp 30s, the wavelength of uviol lamp is
365nm.
Embodiment 2
Step (1): prepare graft a(chondroitin sulfate grafted methacrylic acid methyl ester).
1g chondroitin sulfate (molecular weight is 40000) is added to the aqueous solution of 100ml acetone the (volume of acetone and water
Ratio is for 1:1) in, magnetic agitation dissolves 24h, and rotating speed is 520rpm；Then 1ml methyl methacrylate and 1ml are added wherein
Triethylamine, continues stirring reaction 2 days；Add acetone to be precipitated, and remove unreacted methyl methacrylate and other
The addition volume of small molecule, wherein acetone is 20 times of the aqueous solution volume of acetone；Dissolved with water after being precipitated thing,
Add acetone precipitation, be repeated twice；Finally carry out being vacuum dried 48h in room temperature, vacuum is -100kpa, obtains final product graft a
(chondroitin sulfate grafted methacrylic acid methyl ester, be named as chondroitin sulfate acrylate).
Step (2): aoxidize described graft a.
Weigh 0.9g graft a, be added into 5ml aqueous solution, wait to be completely dissolved, add 0.308g sodium metaperiodate,
Magnetic agitation lucifuge reacts 6h, and the speed of magnetic agitation is 480rpm；Then dialyse 3 days, the molecular cut off of bag filter is
3500；Last lyophilization 3 days, obtains the chondroitin sulfate acrylate aldehyde of white sponge.
Step (3): prepare polymer, the grafting of the graft a after dopamine and oxidation.
Weigh 2g chondroitin sulfate acrylate aldehyde, be added in 100ml round bottom there-necked flask, be subsequently adding 20ml water-soluble
Liquid, treats that it is completely dissolved, and adds 1.9g carbodiimides, and magnetic agitation dissolves, and is adjusted to ph with the sodium hydroxide of 0.1mol/l
5；It is passed through nitrogen 15min after all dissolving, then evacuation 15min, then is passed through nitrogen 15min, then evacuation again
15min, is subsequently adding 0.405g dopamine evacuation 15min, is passed through nitrogen and reacts 24h under the protection of nitrogen, question response is tied
Bundle lucifuge is dialysed three days.The water of dialysis used distilled water, and the ph of water is adjusted to 5, changed within first day a water every 3 hours, second day
Start to change for one day three water, the molecular cut off of bag filter is 1000；Last lyophilization three days, obtains faint yellow spongiform
Polymer (is named as chondroitin sulfate acrylate aldehyde-dopamine).
Step (4): described polymer is dissolved in solvent, irradiating uviol lamp makes crosslinked polymer, that is, described biology is obtained
Binding agent.
Weigh the chondroitin sulfate acrylate aldehyde-dopamine of certain mass, be dissolved in water, configuration concentration is 50%
Solution, wait to be completely dissolved, after obtaining the solution of stable homogeneous, use ultra violet lamp 60s, the wavelength of uviol lamp is 365nm.
Embodiment 3
Step (1): prepare graft a(gelatin graft glycidyl methacrylate).
1g gelatin is added to 50ml phosphate buffered solution (ph=3), mechanical agitation dissolves 24h, rotating speed is
350rpm；Then add 2.2ml glycidyl methacrylate wherein, continue stirring reaction 7 days；Add acetone to carry out
Precipitation, and remove unreacted small molecule, the addition volume of wherein acetone is 20 times of phosphate buffered solution volume；Obtaining
Dissolved with water after precipitate, added acetone precipitation, be repeated twice；Then dialyse 3 days, the molecular cut off of bag filter is
1000；Last lyophilization 3 days, obtains final product graft a(gelatin graft glycidyl methacrylate, is named as gelatin propylene
Acid esters).
Step (2): aoxidize described graft a.
Weigh 0.3g gelatin acrylate, be added into 5ml aqueous solution, wait to be completely dissolved, add the high iodine of 0.308g
Sour sodium, magnetic agitation lucifuge reacts 10min, and the speed of magnetic agitation is 480rpm；Then dialyse 3 days, the retention of bag filter divides
Son is measured as 1000；Last lyophilization 3 days, obtains white or faint yellow spongiform gelatin acrylate aldehyde.
Step (3): prepare polymer, the grafting of the graft a after making a gift of sufficient attachment proteinses and aoxidizing.
Weigh 1g gelatin acrylate aldehyde, be added in 100ml round bottom there-necked flask, be subsequently adding 40ml aqueous solution, treat
It is completely dissolved, and sequentially adds 0.955g carbodiimides, 1.15gn- N-Hydroxysuccinimide, magnetic agitation dissolves, uses
Ph is adjusted to 5.5 by the sodium hydroxide of 0.1mol/l；It is passed through nitrogen 15min after all dissolving, then evacuation 15min, then lead to
Enter nitrogen 15min, then evacuation 15min again, be subsequently adding and make a gift of sufficient attachment proteinses 3 and make a gift of sufficient attachment proteinses 5, be passed through nitrogen and exist
React 24h under the protection of nitrogen, question response terminates to dialyse three days, changed within first day a water every 3 hours, second day starts one day
Change three water, the molecular cut off of bag filter is 1000；Last lyophilization 3 days, obtains spongiform polymer and (is named as gelatin
Acrylate aldehyde-make a gift of sufficient attachment proteinses).
Step (4): described polymer is dissolved in solvent, irradiating uviol lamp makes crosslinked polymer, that is, described biology is obtained
Binding agent.
Weigh the gelatin acrylate aldehyde of certain mass-make a gift of sufficient attachment proteinses polymer, be dissolved in normal saline, join
Put the solution that concentration is 20%, wait to be completely dissolved, after obtaining the solution of stable homogeneous, use ultra violet lamp 30s, the ripple of uviol lamp
A length of 365nm.
In addition, those skilled in the art also can the claims in the present invention scope of disclosure and spirit in do other forms and
Various modifications, interpolation and replacement in details.Certainly, these are made according to present invention spirit various modifications, interpolation and replacement
Deng change, all should be included within scope of the present invention.
Claims (17)
1. a kind of biological adhesive, its contain polymer and solvent it is characterised in that: this polymer is dopamine or make a gift of sufficient adhesion
The graft of the graft a after albumen and oxidation, wherein this graft a is connecing of polymer substance and acrylic ester compound
Branch thing；It is connected with aldehyde radical on hexatomic ring in the polymer substance in graft a after this oxidation；This polymer substance is selected from hyalomitome
At least one in acid, chondroitin sulfate, gelatin, polypeptide, alginic acid and shitosan；This acrylic ester compound is selected from first
One of base acrylate and acrylate.
2. biological adhesive as claimed in claim 1 it is characterised in that: this polymer be produce through ultra violet lamp crosslinked
Polymer.
3. biological adhesive as claimed in claim 1 it is characterised in that: described solvent be water, the aqueous solution of sodium chloride, phosphoric acid
One of salt buffer solution.
4. biological adhesive as claimed in claim 1 it is characterised in that: in this biological adhesive, the percent mass of polymer is dense
Spend for 10%～85%.
5. biological adhesive as claimed in claim 1 it is characterised in that: described aldehyde radical is via on hexatomic ring in polymer substance
Adjacent hydroxyl oxidize formed.
6. a kind of preparation method of biological adhesive, it comprises the steps:
Prepare graft a, this graft a is the graft of polymer substance and acrylic ester compound, wherein this macromolecule
Material is selected from least one in hyaluronic acid, chondroitin sulfate, gelatin, polypeptide, alginic acid and shitosan；This acrylate
Class compound is selected from one of methacrylate and acrylate；
Aoxidize described graft a, make the adjacent hydroxyl oxidize on hexatomic ring in the polymer substance in graft a be aldehyde radical；
Prepare polymer, this polymer is dopamine or the graft making a gift of the graft a after sufficient attachment proteinses and oxidation；
Described polymer is dissolved in solvent, that is, described biological adhesive is obtained.
7. biological adhesive as claimed in claim 6 preparation method it is characterised in that: this prepares the step bag of graft a
Include: described polymer substance is dissolved using solvent m；Acrylic ester compound is added to be reacted, the wherein acrylic acid of addition
The molal quantity of ester type compound is 10-50 times of polymer substance molal quantity；Organic solvent n is added to be precipitated, obtain is heavy
Starch is graft a.
8. biological adhesive as claimed in claim 7 preparation method it is characterised in that: this solvent m be water or water with organic
Solvent, inorganic salt, the mixture of any one in organic acid three, this organic solvent n is acetone or ethanol.
9. biological adhesive as claimed in claim 7 preparation method it is characterised in that: this hyaluronic acid is in solvent m
Mass-volume concentration is 0.001～0.1g/ml；Mass-volume concentration in solvent m for the chondroitin sulfate is 0.001～0.2g/
ml；Mass-volume concentration in solvent m for the gelatin is 0.001～0.25g/ml, mass-volume concentration in solvent m for the alginic acid
For 0.005～0.1g/ml, mass-volume concentration in solvent m for the shitosan is 0.001～0.1g/ml.
10. biological adhesive as claimed in claim 6 preparation method it is characterised in that: aoxidize described graft a step
Including: described graft a is dissolved in the water, adds oxidant to be reacted, this oxidant is sodium metaperiodate, hydrogen peroxide, secondary
One of sodium chlorate；Graft a after oxidation is carried out isolating and purifying, is dried.
The preparation method of 11. biological adhesives as claimed in claim 10 it is characterised in that: aoxidize the step of described graft a
Suddenly, in the solution of middle oxidation reaction, the mass percentage concentration of graft a is 0.1%～10%, when oxidant uses sodium metaperiodate,
The mass percentage concentration of sodium metaperiodate is 1%～20%；When oxidant uses hydrogen peroxide, the mass percentage concentration of hydrogen peroxide is
0.5%～15%；When oxidant uses sodium hypochlorite, the mass percentage concentration of sodium hypochlorite is 0.5%～20%.
The preparation method of 12. biological adhesives as claimed in claim 6 it is characterised in that: the described step preparing polymer
Including: the graft a after described oxidation is dissolved in the water, adds carbodiimides that reactant liquor is obtained, control the ph of reactant liquor
It is worth for 4-6 and add dopamine under the protection of nitrogen or make a gift of sufficient attachment proteinses and carry out reaction and obtain polymer；Prepared is gathered
Compound carries out isolating and purifying, is dried.
The preparation method of 13. biological adhesives as claimed in claim 12 it is characterised in that: the graft a after described oxidation
Being dissolved in the mass percentage concentration after water is 0.1%～10%, and the mass percentage concentration of carbodiimides is the grafting after oxidation
0.5～5 times of thing a mass percentage concentration, dopamine or the mass percentage concentration making a gift of sufficient attachment proteinses are 0.1%～20%.
The preparation method of 14. biological adhesives as claimed in claim 12 it is characterised in that: add during carbodiimides also with
When add n- N-Hydroxysuccinimide, and the mass percentage concentration of n- N-Hydroxysuccinimide be carbodiimides percent mass dense
1～10 times of degree.
The preparation method of 15. biological adhesives as described in claim 10 or 12 it is characterised in that: the step isolating and purifying is equal
Dialysed using the bag filter that molecular cut off is 1000～8000；The step being dried is all using lyophilization.
The preparation method of 16. biological adhesives as claimed in claim 6 it is characterised in that: the method also includes will be described poly-
Compound is irradiated the step that uviol lamp makes crosslinked polymer after being dissolved in solvent.
The preparation method of 17. biological adhesives as claimed in claim 16 it is characterised in that: the wavelength of uviol lamp is 200～
400nm, the time of irradiation is 10s～3600s.
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