CN108586682A - Dissaving polymer and preparation method thereof - Google Patents

Dissaving polymer and preparation method thereof Download PDF

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CN108586682A
CN108586682A CN201710156154.3A CN201710156154A CN108586682A CN 108586682 A CN108586682 A CN 108586682A CN 201710156154 A CN201710156154 A CN 201710156154A CN 108586682 A CN108586682 A CN 108586682A
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polymer
dissaving polymer
reaction
dissaving
preparation
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CN108586682B (en
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王文新
郭琳茹
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Tianjin University
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Abstract

The present invention discloses dissaving polymer and preparation method thereof, homopolymerization is carried out by monomer of polyethyleneglycol diacrylate, it polymerize polyethyleneglycol diacrylate using reverse enhancing atom transfer radical polymerization method, in the starting stage of reaction, the monoadduct and oligomer of the monomer and initiator that are primarily present in polymeric system, with the progress of reaction, distribution of polymer gradually broadens.Mark's Huo Wenke formula constants of dissaving polymer are 0.36-0.4.Hyperbranched polymer structure is fine and close, shows spherical structure, and show degradable and good biocompatibility.

Description

Dissaving polymer and preparation method thereof
Technical field
The invention belongs to new bio field of medical materials, relate generally to dissaving polymer and preparation method thereof.
Background technology
Wound dressing is to treat the major way of acute and chronic wound.In recent decades, according to different traumatic events A variety of special wound dressings have been invented in research.Wherein as one kind in novel wound dressing, hydrogel wound dressing is because of table Face is smooth, good biocompatibility, is tightly combined with the out-of-flatness surface of a wound, promotes the advantages that epithelial cell growth and obtained extensively It uses.But now widely used synthetic hydrogel dressing poor, mechanical property and wound in the prevalence of wound tissue's adhesive force The problems such as mouth tissue mismatches and bio-toxicity is larger.The study found that the polymer used by controlling synthetic hydrogel The achievable performance for improving synthetic hydrogel wound dressing such as ingredient, structure, the degree of polymerization.In control polymer architecture and performance side Face, multi-vinyl monomer are conveniently easy to get and it is concerned with multiple reaction site due to it.Especially more vinyl lists The polymer of syntaxy has a large amount of unreacting ethylene group, can further be modified acquisition and preset functional group, optimization biofacies Capacitive and bioadhesive etc. provide possibility for its application in aerogel dressing.
But the polymerization of multi-olefin monomer is always a major challenge that the field of polymers faces, famous before more than 70 years Theoretical (F-S the is theoretical) predictions of Flory-Stockmayer：The polymerization of multi-vinyl monomer can extremely low monomer conversion (< 10%) reach gel point under and form gel, and the theory is confirmed by extensive experiment.But it is mostly anti-due to multi-vinyl monomer Answer site, control the polymerization process of multi-vinyl monomer not only can delayed gel point, or even the poly- of novel labyrinth can be obtained Close object.The polymer of multi-vinyl monomer synthesis has the vinyl of special cyclized structure and high level and makes it through changing Extensive use can be obtained after property.And the report for preparing hydrogel material about multi-vinyl monomer homopolymerization at present is still less.
Invention content
It is an object of the invention to overcome the deficiencies of the prior art and provide dissaving polymers and preparation method thereof, pass through Reverse enhancing atom transfer radical polymerization method (in situ DE-ATRP) homopolymerization polyethyleneglycol diacrylate (PEGDA700) synthesize dissaving polymer poly (PEGDA700)HP, and its aqueous solution is prepared into hydrogel wound dressing.System Standby hydrogel material has higher storage modulu G', stronger tissue adhension ability, degradable and good bio-compatible Property, it is expected to be used in wound dressing, tissue adhesive and bioengineering as new material.
The technical purpose of the present invention is achieved by following technical proposals：
Dissaving polymer carries out homopolymerization by monomer of polyethyleneglycol diacrylate, utilizes reverse enhancing atom transfer Free radical polymerisation process polymerization polyethyleneglycol diacrylate is primarily present in the starting stage of reaction in polymeric system The monoadduct and oligomer of monomer and initiator, with the progress of reaction, distribution of polymer gradually broadens, the master occurred at this time If the cross-linking reaction of low-molecular weight oligo object, since monomers most at this time has been depleted, so being more easy to that molecule occurs Between branching reaction and non-linear growth, finally obtain the dissaving polymer with highly -branched degree.
The number-average molecular weight of polyethyleneglycol diacrylate is 700.
The weight average molecular weight of dissaving polymer is 10KDa -40KDa, PDI 1.65-4.13.
The contents of ethylene of dissaving polymer is 28-35%.
The degree of branching of dissaving polymer is 66-72%.
Mark's-Huo Wenke formula constants of dissaving polymer are 0.36-0.4.
Hyperbranched polymer structure is fine and close, appears similar to the spherical structure of a diameter of 5.367 ± 1.2nm.
The preparation method of dissaving polymer, by polyethyleneglycol diacrylate, 2 bromo 2 methyl propionic acid ethyl ester, CuCl2 And N, N, N ', N ", N "-pentamethyl-diethylenetriamine are according to molar ratio 80：40：(1—1.2)：(1.8-2) are placed in butanone Even dispersion, and the L-AA of copper chloride molal quantity half is added, it is reacted under the conditions of deoxygenation, it is former using reverse enhancing Sub- transfer radical polymerization method polymerize polyethyleneglycol diacrylate, main in polymeric system in the starting stage of reaction The monoadduct and oligomer of existing monomer and initiator, with the progress of reaction, distribution of polymer gradually broadens, sends out at this time The cross-linking reaction of raw mainly low-molecular weight oligo object, since monomers most at this time has been depleted, so being more easy to send out Raw intermolecular branching reaction and non-linear growth, finally obtain the dissaving polymer with highly -branched degree.
When carrying out the preparation of dissaving polymer, reaction temperature is 50-70 degrees Celsius, preferably 50-60 degrees Celsius；Instead It is 0.5-4.5 hours, preferably 1-3 hours between seasonable.
Hydrogel based on dissaving polymer will be obtained super using reverse enhancing atom transfer radical polymerization method Branched polyethylene glycol diacrylate is as presoma, and with 2,2- dimethoxy-phenylf acetophenones for ultraviolet initiator, water is Solvent, it is hydrogel material to cause carbon-carbon double bond in presoma under ultra violet lamp to carry out crosslinking.
The mass ratio of presoma and photoinitiator is 100：(1—1.2).
A concentration of 10-the 30wt% of presoma, the i.e. volume (μ L) of forerunner's weight (mg)/water.
Ultra violet lamp intensity is 1-2W/cm2, preferably 1.5-1.7W/cm2.The ultra violet lamp time is 10-20s.
Crosslinking temperature is 20-25 degrees Celsius of room temperature.
Technical solution of the present invention is polymerize using reverse enhancing atom transfer radical polymerization method (in situ DE-ATRP) Polyethyleneglycol diacrylate PEGDA700Dissaving polymer poly (PEGDA are synthesized700)HP, and consolidated by photo-crosslinking Turn to hydrogel material.In order to which hydrogel material is used for wound dressing, its mechanical property, Lap- are characterized by rheometer The means such as shear, Pull-off and Burst test evaluate its tissue adhension performance, and swelling, degradation and cytotoxicity experiment are into one The biocompatibility of step characterization hydrogel material.The hydrogel material of preparation has higher storage modulu G', stronger tissue Adhesive capacity, degradable and good biocompatibility, be expected to be used for as new material wound dressing, tissue adhesive and In bioengineering.
Description of the drawings
Fig. 1 is the polymerization principle schematic of ATRP.
Fig. 2 is the side of the dissaving polymer prepared using reverse enhancing atom transfer radical polymerization method in the present invention Method is illustrated
Fig. 3 be gel permeation chromatography test chart in the embodiment of the present invention (hyperbranched polymer molecule amount changes over time figure, Abscissa is GPC retention times).
Fig. 4 is the nuclear magnetic resonance spectroscopy test spectrogram of different molecular weight dissaving polymer in the embodiment of the present invention.
Fig. 5 is mark's-Huo Wenke formula constant alpha tests of the dissaving polymer of different molecular weight in the embodiment of the present invention Result schematic diagram.
Fig. 6 is laser particle distribution tests (LPSD) result figure of the embodiment of the present invention, and abscissa is size, indulges and sits It is designated as percentage composition.
Fig. 7 is the dissaving polymer rheometer test curve graph of different molecular weight in the embodiment of the present invention, and wherein a is shake - time photo-crosslinking is swung, b is concussion-frequency mode.
Fig. 8 is the swelling behavior of different molecular weight and a concentration of 30% hyperbranched hydrogel material in the embodiment of the present invention Test curve figure.
Fig. 9 is the degradation property of the hyperbranched hydrogel material of a concentration of 30% different molecular weight in the embodiment of the present invention Test curve figure.
Specific implementation mode
The technical solution further illustrated the present invention with reference to specific embodiment, experimental raw and instrument refer to following table.
Experimental raw
Laboratory apparatus
Using reverse enhancing atom transfer radical polymerization method (in situ DE-ATRP), base in the present invention In the basis of ATRP.The polymerization principle of ATRP is as shown in Figure 1, wherein M is monomer, MnIt is the polymeric chain of n unit composition；Mnt For reduction-state transition metal complex；R-X is initiator (halogenated compound)；Mn+1T is oxidation state transition metal complex compound；R— M, R-MnIt is reactive species, R-M-X, R-Mn- X is suspend mode kind.In initiating stage, it is in the CuX of low-oxidation-state (X is halogen atom) and 2,2 '-bipyridines (bpy complex compounds) snatched away from R-X halogen atom generate primary group of free radicals R and CuX/bpy high oxidation state complex compound suspend mode kinds.Reactive species are to cause monomer by primary group of free radicals to generate, it can continue to cause Monomer realizes active free radical polymerization, and can capture halogen atom from CuX/bpy high oxidation state complex compounds and become suspend mode kind. When polymerization, the reversible transformation balance being carried out at the same time between suspend mode kind and living radical, until polymer reaches predetermined molecules Amount.Because in such reaction, halogen atom is contained from halide to high oxidation state metal complex compound, then again from high oxidation state Metal complex is to the reversible transfer of the atom of free radical, and reactivity kind is free radical, therefore this type of polymerization is referred to as For atom transfer radical polymerization.In situ DE-ATRP polymerizations are increased in ATRP by additional bivalent cupric ion concentration Deactivation rate (inversely enhances atom transfer radical polymerization, DE-ATRP) so that the homopolymerization of multi-vinyl monomer is in power Learn the lower progress of control.
Utilize method such as Fig. 2 of dissaving polymer prepared by reverse enhancing atom transfer radical polymerization method：
(1) precise polyethyleneglycol diacrylate (PEGDA successively700, 24mmol, 16.80g), butanone (43.00mL), CuCl2Solution (0.3mmol, 40.34mg), 2 bromo 2 methyl propionic acid ethyl ester (EBriB, 12mmol, 1780.02 μ L), two mouthfuls of circles of 100mL are added in N, N, N ', N ", N "-pentamethyl-diethylenetriamine (PMDETA, 0.6mmol, 103.98 μ L) In the flask of bottom.Wherein PEGDA700:EBriB:CuCl2:PMDETA=80:40:1:2.Successively respectively with the rubber stopper cleaned up It is sealed with sealed membrane, leads to argon gas 15min with deoxygenation.At the same time, L-AA (AA) is configured to a concentration of 100mg/mL Aqueous solution, wait for using after deoxygenation.
(2) after deoxygenation 15min, the rapid AA solution 264.18 opened one of round-bottomed flask bottleneck and take configuration μL(0.15mmol,1/2*CuCl2) be added in reaction system, it is again sealed off, continues deoxygenation 1min or so.It, will after deoxygenation Two mouthfuls of round-bottomed flasks are placed in 50 DEG C, in the oil bath heater of 700r/min, start reaction and timing.
(3) when being spaced the identical time, first lead to argon gas, then with clean up 5mL syringes merging liquid level hereinafter, Sample is set to flow in syringe by positive pressure.When sample size reaches 2mL, syringe is taken out and then stops leading to argon gas.It will obtain Sample be placed in the disposable vial of 20mL, and mark.100 μ L samples are therefrom taken with liquid-transfering gun and with DMF (dimethyl methyls Amide) it is diluted to 1mL, it is sufficiently mixed uniformly.Small-sized alumina column is selected, DMF is used in combination to soak, then the polymerization after filtering dilution Object sample removes Cu therein.Sample can be observed at this time by light blue bleach.Later with the filter mistake of a diameter of 0.4mm Sample is filtered, finally sample is positioned in GPC test bottles, and labeled test.
(4) by the progress of GPC monitoring reactions, when molecular weight achieves the goal molecular weight, by two mouthfuls of round-bottomed flasks from oil It is taken out in bath heater, and opens the bottleneck of sealing, it is made fully to be contacted with air.In the large beaker of the 1000mL cleaned up The 5-7 times of ether for reacting stoste volume of middle addition, setting speed 600r/min.It is under conditions of high-speed rotation, reaction is former Liquid is added dropwise to by separatory funnel in ether and is sealed with tinfoil by beaker dropwise.After completion of dropwise addition, continue to stir the left sides 30min The right side stands 5-7h at room temperature.When liquid stratification to be mixed and more as clear as crystal upper liquid, supernatant liquor is poured out.Continue The ether of 3-5 times of subnatant volume of addition in the state of high-speed stirred, stir about 30min in the state that tinfoil seals, then Secondary stratification.Repeatedly twice after, the polymer viscosity of lower layer gradually increases and is adhered to beaker bottom.
(5) medium-sized alumina column is selected, a small amount of cotton and sand is first sequentially added, it is made to pave.Then it is added about The alumina powder of 3/5 alumina column height, prepares alumina filter column.It is soaked with acetone using preceding.With a small amount of third It is gathered in the polymer of beaker bottom after ketone dilution precipitation, is fully poured into alumina filter column along post jamb after dissolving, with weighing The disposable vial of good quality collects filtered limpid polymer solution.
(6) all products being collected into after filtering are all sealed with tinfoil to and uniformly pricked upper aperture, are then placed into true Empty drying box removes solvent, obtains transparent straight polymer.Then it weighs, calculates yield.
If gel permeation chromatography (GPC) test result of Fig. 3 is it is found that in the starting stage of reaction, polymer is in multiple lists Peak is distributed, this shows the monoadduct and oligomer for the monomer and initiator being primarily present in polymeric system.With reaction It carries out, distribution of polymer gradually broadens (PDI 1.65-4.13), the crosslinking of the mainly low-molecular weight oligo object occurred at this time Reaction.Since monomers most at this time has been depleted, so it is more easy to occur intermolecular branching reaction and non-linear growth, The dissaving polymer with higher branch degree is finally obtained.In the present invention respectively by molecular weight be 10kDa, 20kDa, The dissaving polymer of 40kDa is named as H1, H2, H3.
The reaction result of the dissaving polymer of 1 different molecular weight of table
Fig. 4 is the nuclear magnetic resonance spectroscopy test of different molecular weight dissaving polymer, it is known that containing a large amount of in polymer Vinyl-functional can calculate its contents of ethylene and the degree of branching (Zhao T, Zhang H, Zhou D, et al.Water soluble hyperbranched polymers from controlled radical homopolymerization of PEG diacrylate[J].RSC Advances.2015,5(43):33823-33830).The content of polymer medium vinyl and The degree of branching can be calculated by formula (1) with (2).
Wherein a, d and d ' respectively represent respective peak value (size at peak, i.e. peak area).As seen from the results in Table 1, hyperbranched poly Close object medium vinyl content reduces (H1 with the growth of its molecular weight:33.93%, H2:29.20%, H3:28.35%) it, props up Change degree increases (H1 with the growth of molecular weight:66.07%, H2:70.80%, H3:71.65%).This is because causing when improving When agent is with monomer ratio, initial reaction stage forms a large amount of extremely short elementary chains, high polymer concentration and low polymeric chain diameter It promotes intermolecular reaction and inhibits the rate of intramolecular cyclization reaction, is i.e. vinyl on a polymer chain is more easy to enter In the growth boundary of other strands, intermolecular mutual crosslinking is simultaneously generated with higher branch degree and a large amount of vinyl-functionals Dissaving polymer.
The conformation of polymer in a solvent is related with its mark's-Huo Wenke formula constant α.As α≤0.5, polymer is in Existing comparatively dense structure.As 0.5≤α≤0.8, random coil conformation is presented in polymer；And polymer coil more stretches, α is closer to 0.8；When polymer is in rigid Coiling-type, 1≤α.The α values of polymer can (poor refractive power be examined by tri- kinds of detectors of GPC Survey RI, viscosity detector VS and Laser Light Scattering detector LS) combination measure.By the test result of Fig. 5 it is found that hyperbranched poly Mark's-Huo Wener the constant αs for closing object are 0.36-0.40, and it is spherical that this shows that the polymer architecture to be formed is similar to.The laser of Fig. 6 Particle diameter distribution tests (LPSD) result and shows that the grain size of dissaving polymer is 5.367 ± 1.2nm.In conclusion using in Situ DE-ATRP polymerizations polymerize dissaving polymer of the polyethyleneglycol diacrylate synthesis with higher branch degree, and The polymer architecture is fine and close, appears similar to the spherical structure of a diameter of 5.367 ± 1.2nm.
By1H-NMR test results are it is found that the content of dissaving polymer medium vinyl functional group is more and PEGDA is water Dissolubility, thus after being mixed with photoinitiator under ultra violet lamp can Quick cross-linking be hydrogel material and be expected to be used as tissue Engineering or bioadhesive.Can have by the test of rheological property, adhesion property, swelling behavior, degradation property and biocompatibility The physical property and biological property of the characterization of the body hydrogel material.
Respectively using the different dissaving polymer of molecular weight as presoma, 2,2- dimethoxy-phenylf acetophenones (Irgacure2959) be ultraviolet initiator, water is solvent, using Light lnduced Free Radicals polymerisation be prepared for it is a series of not With the hydrogel material of concentration.Specific preparation method is as follows：According to table 2, configure the dissaving polymer of different molecular weight to The aqueous solutions of polymers of various concentration is placed in disposable vial and fully dissolves.Since Irgacure 2959 is in pure water In dissolubility it is very poor, therefore be dissolved in acetone, and with being that 2959/ acetone of Irgacure that mass concentration is 5% is molten Liquid takes the solution of respective volume to be added in aqueous solutions of polymers before photo-crosslinking with liquid-transfering gun, is shaken with vortex instrument rapidly mixed It is even.It takes the colourless transparent solution of appropriate volume to be placed in corresponding container, is put under UV lamp, be solidified under certain illumination condition Hydrogel.
Table 2 prepares the rate of charge of hydrogel material
The rheological property of polymer and the ultraviolet research for causing solidification plastic can be by the plate (d=that are controlled by pressure 8mm) AR2000 rheometers are realized.It is 320-390nm, light intensity using wavelength in the research of photo-crosslinking rheological property Degree is 100mW/cm21000 type ultraviolet lamps of Omnicure.In test process, ultraviolet light may pass through the chassis of PMMA, so poly- Closing object can be by ultraviolet lighting until plastic.This test is at room temperature 5Hz in frequency after photo-crosslinking 20s, and it is 5% to strain, It is tested under concussion-temporal mode that height is 0.8mm.The mixed with polymers solution configured is placed on testboard, into The steady testing of row 1min then carries out ultraviolet light cross-linking 20s.After the completion of to be tested, the shake that can be 0.1 to 100Hz in frequency Swing-frequency mode under further test the storage modulu G' and loss modulus G " of hydrogel material.
Under earthquake-time test pattern, the storage modulu G' and loss modulus G " of aqueous solutions of polymers are in preceding 1min Without significant change.After ultraviolet lighting, the G' of polymer starts to sharply increase and be far longer than G ", and G' and G " occurs in 10 seconds Intersection point shows the formation of hydrogel material.From Fig. 7 (a) it is found that the uncrosslinked polymerization of modular ratio of the hydrogel material after crosslinking High 3 orders of magnitude of the modulus of object, and reach steady state value and do not change over time.This has further demonstrated that dissaving polymer can Rapid polymerization and it is fully formed hydrogel material in 20s.In addition, the G' of dissaving polymer is dropped with the increase of molecular weight Low (H1:66kPa,H2:58kPa,H3:52kPa), this is because with reaction progress, contents of ethylene with molecular weight increasing Add and reduce, result in the decline of crosslink density, shows as the reduction of G'.
Dissaving polymer is because having fine and close structure and higher contents of ethylene, therefore its crosslink density is high and shows With higher G'.Under earthquake-frequency test pattern, the stability of hydrogel material is further characterized.Such as Fig. 7 (b) institutes Show, under the conditions of the test frequency of 0.01Hz to 256Hz, the modulus of the dissaving polymer (0.01Hz- in the frequency range 200Hz) it is always maintained at stabilization.Further demonstrate that the structure of dissaving polymer is relatively stablized, this is polymer architecture and crosslinking The coefficient result of density.
In order to characterize the adhesion property of hydrogel material, can by Lap-shear, Pull-off, Burst test respectively from Laterally adherency, longitudinal adherency and impact resistance degree carry out the characterization of mechanics adhesion property.
Lap-shear is tested
Setup test sample is needed before carrying out Lap-shear tests.Specific preparation process is as follows：
1) mixed with polymers solution is configured：The straight polymer of different structure, different molecular weight is respectively configured as different dense Spend the aqueous solutions of polymers of (10%, 20%, 30%, 50%w/v)；Then ultraviolet initiator Irgacure 2959 is configured At a concentration of 5% acetone soln.It is 100 according to the mass ratio of polymer and photoinitiator:1 ratio is uniformly mixed.
2) preparation of adhered test sample：Pretreated pigskin is cut to long 40mm, wide 25mm, the shape of thick 1mm is used Its fatty side is sticked to long 75mm by Superglue, wide 25mm, on the sheet glass of thick 1mm.Then gathering for 200 μ L is taken with liquid-transfering gun Closing object mixed solution makes it uniformly be laid on pigskin epidermis.Take an equal amount of sheet glass that it is made gently to be covered in polymerization again On object mixed solution.(the intensity under default light intensity and time conditions：0.8,1.2,1.7W/cm2；Time：10s, 15s, 20s), And ultraviolet lamp is away from progress photo-crosslinking solidification at the sheet glass 1cm of upper layer.After photo-crosslinking, sample places 2- at ambient temperature Lap-shear tests are carried out after 3min again.
3) Lap-shear is tested：The test sample that will be prepared, it is parallel in vertical direction to be placed on test machine. It is stretched under the constant speed of 2mm/min, until fracture.Adhesion strength is the maximum value before fracture, and every group of test repeats 3 It is secondary.
Pull-off is tested
Setup test sample is needed before carrying out Pull-off tests.Specific preparation process is as follows：
1) mixed with polymers solution is configured：The straight polymer of different structure, different molecular weight is respectively configured as different dense Spend the aqueous solutions of polymers of (10%, 20%, 30%, 50%w/v)；Then ultraviolet initiator Irgacure 2959 is configured At a concentration of 5% acetone soln.It is 100 according to the mass ratio of polymer and photoinitiator:1 ratio is uniformly mixed.
2) preparation of adhered test sample：Pretreated pigskin is cut to diameter 25mm, the disc of thick 1mm is used Its fatty side is sticked on the aluminium flake of a diameter of 25mm by Superglue.Then the mixed with polymers solution of 100 μ L is taken with liquid-transfering gun It is set uniformly to be laid on pigskin epidermis.Again with long 75mm, it is mixed that the sheet glass of wide 25mm, thick 1mm is gently covered in polymer It closes on solution.(the intensity under default light intensity and time conditions：1.7W/cm2；Time：20s), and ultraviolet lamp is away from upper layer sheet glass Photo-crosslinking solidification is carried out at 1cm.After waiting for photo-crosslinking, with Superglue by the aluminium flake station of same size on the glass sheet.Sample Product carry out Pull-off tests again after placing 2-3min at ambient temperature.
3) Pull-off is tested：The test sample that will be prepared, it is parallel in horizontal direction to be placed on test machine.In 2mm/ It is stretched under the constant speed of min, until fracture.Adhesion strength is the maximum value before fracture, and every group of test is repeated 3 times. Burst is tested
Setup test sample is needed before carrying out Burst tests.Specific preparation process is as follows：
1) mixed with polymers solution is configured：The straight polymer of different structure, different molecular weight is respectively configured as different dense Spend the aqueous solutions of polymers of (10%, 20%, 30%, 50%w/v)；Then ultraviolet initiator Irgacure 2959 is configured At a concentration of 5% acetone soln.It is 100 according to the mass ratio of polymer and photoinitiator:1 ratio is uniformly mixed.
2) preparation of adhered test sample：Pretreated pigskin is cut to diameter 30mm, the disc of thick 1mm is used Its greasy is fixed on the surface of Burst test pumps by Superglue, and pricks an aperture on the surface of pigskin, upper small with pump Hole site is parallel, in the same size.Open tap, adjust flow velocity allow the water in the form of water column spray and record at this time just Beginning pressure P0.It closes tap and removes the water of pig skin surfaces.Then the mixed with polymers solution of 200 μ L is taken to make it with liquid-transfering gun Uniformly it is laid on pigskin epidermis.(the intensity under default light intensity and time conditions：1.7W/cm2；Time：20s), and it is ultraviolet Lamp is away from progress photo-crosslinking solidification at the sheet glass 1cm of upper layer so that water-setting is adhesive on pigskin.After waiting for photo-crosslinking, in room temperature Under the conditions of place 2-3min after carry out Burst tests again.
3) Burst is tested：Tap is opened, is tested under the conditions of preset flow rate, until aquagel breaks, water column spray Go out, record maximum pressure value Pt.Then maximum adhesion intensity is P=Pt-P0, every group of test be repeated 3 times.
By Lap-shear, Pull-off, known to Burst test results (table 3), in 1.7W/cm2, the photo-crosslinking item of 20s Under part, have the adhesion strength of the hyperbranched hydrogel of identical molecular weight with the increase of polymer concentration (10%, 20%, 30%) And increase.When molecular weight is 10kDa, the Lap-shear adherency of a concentration of 10%, 20%, 30% hyperbranched hydrogel is strong Degree be respectively 6.61kPa, 10.25kPa, 18.89kPa, Pull-off adhesion strengths be respectively 3.45kPa, 6.26kPa, 9.88kPa.When molecular weight is K2, K3, identical variation tendency is shown.This is because second in the higher polymer solution of concentration Amount vinyl content is higher, and crosslink density is also higher.
3 1.7W/cm of table2The adhesion property test of hyperbranched hydrogel material under 20s crosslinking conditions
When polymer concentration is identical, the adhesion strength of hyperbranched hydrogel is reduced with the increase of polymer molecular weight. When a concentration of 30%, the Lap-shear adhesion strengths of the hyperbranched hydrogel of molecular weight 10kDa, 20kDa, 40kDa are respectively 18.89kPa, 15.03kPa, 9.75kPa, Pull-off adhesion strengths are respectively 5.39kPa, 3.89kPa, 2.97kPa, Burst Adhesion strength is respectively 0.395MPa, 0.347MPa, 0.294MPa.This is because branching consumes portion with intermolecular reaction Divide vinyl, reduces crosslink density, the conclusion is identical as the result of hydrogel rheology testing.In conclusion hyperbranched The Lap-shear intensity of hydrogel reaches as high as 18.89kPa, and for Pull-off intensity up to 9.88kPa, Burst intensity is reachable 0.395MPa.It follows that the hydrogel has compared with strongly adherent energy, it is expected to be used as wound dressing.
Polyalcohol hydrogel is made of water and polymer network structure, it can absorb a certain amount of moisture and be swollen For swollen hydrogel.The swelling ratio of equilibrium state can be considered a direct parameter of characterization crosslinked polymer degree, therefore can pass through Equilibrium swelling experiments characterize the structure feature of polymer.Swelling ratio can change with the difference of the degree of cross linking.
Swelling behavior characterizes
The test of swelling behavior performance can be measured with weight method.Detailed process is as follows：
1) preparation of hydrogel：Configure the polymer of different structure, different molecular weight in a concentration of 30% polymer Then a concentration of 5% 2959 solution of photoinitiator Irgacure, mass ratio 100 is added in solution:1.Take the mixing of 50 μ L Object solution is placed on the sheet glass weighed, and is 1.7W/cm in intensity2, time 20s, highly to carry out light under conditions of 1cm Crosslinking curing.After waiting for photo-crosslinking, hydrogel of weighing at once, and it is denoted as initial weight W0, then place it in the PBS of 2mL In buffer solution, it is placed in 37 DEG C of shaking table and is rocked with slow speed.
2) it weighs：The hydrogel of swelling is regularly taken out from PBS buffer solution, gently wipes excess surface moisture and is claimed Weight, is denoted as Wt.Then hydrogel is placed back in PBS buffer solution.The swelling ratio (SR) of hydrogel can be counted by formula (3-1) It calculates：
SR=(Wt-W0)/W0× 100% (formula 3-1)
Each hydrogel takes four samples to be tested, and averages, and is denoted as final swelling ratio SR.
In order to evaluate the swelling behavior of hydrogel in physiological conditions, the hydrogel prepared is immersed in PBS when test In 24 orifice plates of buffer solution, it is placed in 37 DEG C of shaking table.Swelling ratio by hydrogel material weight change in certain time come It calculates.Test results are shown in figure 8 for swelling, and the stage swelling in the early stage of hyperbranched hydrogel is very fast and reaches at 15 days or so Equilibrium state.When polymer molecular weight is respectively 10kDa, 20kDa, 40kDa, the swelling ratio point when hyperbranched hydrogel balances It Wei 31.62%, 35.22%, 37.48%.This is because there is fine and close branch because the degree of branching is higher in dissaving polymer Change structure.Hydrone hardly enters intermolecular and so that strand is expanded, therefore swelling ratio is relatively low.
Should have generally, for the ideal biomaterial that most of organizational projects are applied adjustable, relatively stabilization Degradation property.Under oxidation reaction, radiation, thermal decomposition or hydrolysis, main chain or side chain occur fracture and cause polymer The degradation of polymer.Wherein, the degradation that polymer occurs by hydrolysis is regarded as the main chain in polymer, oligomer or The fracture of chemical bond has occurred between monomer under hydrolysis.
Degradation property characterizes
The test of hydrogel degradation property can be measured with weight method.Detailed process is as follows：
1) preparation of hydrogel：Configure the polymer of different structure, different molecular weight in a concentration of 30% polymer Then a concentration of 5% 2959 solution of photoinitiator Irgacure, mass ratio 100 is added in solution:1.Take the mixing of 50 μ L Object solution is placed on the sheet glass weighed, and is 1.7W/cm in intensity2, time 20s, highly to carry out light under conditions of 1cm Crosslinking curing.It after waiting for photo-crosslinking, places it in the PBS buffer solution of 2mL, is placed in 37 DEG C of shaking table with slow speed It rocks.One group therein (4) hydrogel is taken, is freeze-dried, is weighed when reaching constant weight, be denoted as initial weight W0。
2) it weighs：Hydrogel is regularly taken out from PBS buffer solution records weight when freeze-dried processing is up to constant weight Wt.Residual qualities percentage digit rate can be calculated by formula (3-2) after hydrogel degradation：
Massloss=(W0-Wt)/Wt× 100% (formula 3-2)
Each hydrogel takes four samples to be tested, and averages, and is denoted as final residual qualities percentage.
Because there are ester functional groups in polymer, can degrade because of hydrolysis after being immersed in PBS buffer solution, Experimental result is as shown in Figure 9.Hyperbranched hydrogel shows larger degradation behavior, this is that polymer is shorter by much containing What PEG chains were constituted under branching reaction, degradation reaction occurs mainly in the fracture of ester group in shorter side chain, final polymer drop Solution is the smaller oligomer of molecular weight.When polymer molecular weight difference, degradation behavior is also varied from.Work as polymer molecule Amount is respectively 10kDa, when 20kDa, 40kDa after polymer degradation residual polymer mass fraction be 43.19%, 48.74%, 52.96%.The main reason for this variation tendency with polymer molecular weight increase, polymer formed structure relative to point Son measures more fine and close for smaller polymer, the opposite decrease of hydrolysis, degradation capability reduction, the quality point of residual polymer Number relative increase.In conclusion degradable dissaving polymer is likely to be suitable for the wound dressing or tissue to heal in short term Adhesive.
In order to characterize the biocompatibility of hydrogel material, can be existed by fibroblast (Fibroblast) metabolic activity StandardUnder the conditions of test.After cultivating mouse 3T3 fibroblasts under standard cell culture conditions for 24 hours, It is put into the hydrogel material of photo-crosslinking preparation.After continuing culture 24 hours, takes out hydrogel material and be used in combinationMethod To test its cytotoxicity.
Test result is as shown in table 4, and the cytotoxicity of hydrogel material is different due to the difference of polymer molecular weight.When poly- When adduct molecule amount changes, the cytotoxicity of hydrogel material is reduced with the increase of polymer molecular weight.As molecular weight is The cell survival rate of the hyperbranched hydrogel of 10kDa, 20kDa, 40kDa is respectively 82.6%, 83.9%, 86.9%.Although super Branched polymer medium vinyl content is higher, but some is embedded in branched structure, therefore dissaving structure hydrogel With lower cytotoxicity.
The cytotoxicity test of the hyperbranched hydrogel material of the different molecular weight of Fig. 4 a concentration of 30%
This patent passes through atom transfer radical polymerization (in situ DE-ATRP) homopolymerization PEGDA for inversely enhancing700It is single Body obtains dissaving polymer poly (PEGDA700)HP.The formation of its dissaving structure is anti-dependent on the polymerization of dynamics Controlling It answers, intermolecular reaction is promoted, and intramolecular cyclization reaction is suppressed.The characterization of polymer proves that the α of dissaving polymer is small In 0.5, structure is similar to spherical.Aqueous solutions of polymers solidification can be prepared hydrogel material by ultraviolet light cross-linking.It is logical Cross ultraviolet light-rheology joint test it is found that dissaving polymer can it is fast rapid-result (<20s) and highly branched structure and a large amount of ethylene Base makes it have higher storage modulu G'.Pass through Lap-shear, Pull-off and Burst test evaluation hydrogel material Tissue adhension performance finds that hyperbranched hydrogel has higher adhesion strength.In addition, hyperbranched hydrogel is with lower molten Swollen performance and readily degradable energy.By cytotoxicity test it is found that hyperbranched hydrogel has preferable cell compatibility.To sum up It is described, dissaving polymer prepare hydrogel material because have higher modulus, the structure of stabilization, excellent adhesion strength, Moderate swelling and degradation property, preferable biocompatibility and as a kind of potential group weaver's adhesive.I.e. in the present invention Dissaving polymer and based on the hydrogel of dissaving polymer as the application in wound dressing or tissue adhesive.
Technological parameter is recorded according to the content of present invention to be adjusted, and can prepare the dissaving polymer of the present invention and is based on The hydrogel of dissaving polymer shows the performance almost the same with embodiment.The present invention has been done above and has illustratively been retouched It states, it should explanation, in the case where not departing from core of the invention, any simple deformation, modification or other abilities Field technique personnel can not spend the equivalent replacement of creative work to each fall within protection scope of the present invention.

Claims (10)

1. dissaving polymer, which is characterized in that carry out homopolymerization by monomer of polyethyleneglycol diacrylate, utilize reverse enhancing Atom transfer radical polymerization method polymerize polyethyleneglycol diacrylate, main in polymeric system in the starting stage of reaction The monoadduct and oligomer of existing monomer and initiator are wanted, with the progress of reaction, distribution of polymer gradually broadens, over-expense The weight average molecular weight of fluidized polymer is 10KDa -40KDa, PDI 1.65-4.13.
2. dissaving polymer according to claim 1, which is characterized in that the equal molecule of number of polyethyleneglycol diacrylate Amount is 700.
3. dissaving polymer according to claim 1, which is characterized in that the contents of ethylene of dissaving polymer is 28-35%, the degree of branching is 66-72%.
4. dissaving polymer according to claim 1, which is characterized in that mark-Huo Wenke of dissaving polymer is public Formula constant is 0.36-0.4.
5. dissaving polymer according to claim 1, which is characterized in that hyperbranched polymer structure is fine and close, shows Similar to the spherical structure of a diameter of 5.367 ± 1.2nm.
6. the preparation method of dissaving polymer, which is characterized in that by polyethyleneglycol diacrylate, 2 bromo 2 methyl propionic acid Ethyl ester, CuCl2And N, N, N ', N ", N "-pentamethyl-diethylenetriamine are according to molar ratio 80：40：(1—1.2)：(1.8-2) are set It is evenly dispersed in butanone, and the L-AA of copper chloride molal quantity half is added, it is reacted, is utilized under the conditions of deoxygenation Reverse enhancing atom transfer radical polymerization method polymerize polyethyleneglycol diacrylate, in the starting stage of reaction, polymer The monoadduct and oligomer of the monomer and initiator that are primarily present in system, with the progress of reaction, distribution of polymer is gradual It broadens, the cross-linking reaction of low-molecular weight oligo object occurs at this time, since monomers most at this time has been depleted, be more easy to occur Intermolecular branching reaction and non-linear growth, finally obtain the dissaving polymer with highly -branched degree.
7. the preparation method of dissaving polymer according to claim 6, which is characterized in that carrying out dissaving polymer Preparation when, reaction temperature be 50-70 degrees Celsius, the reaction time be 0.5-4.5 hours.
8. the preparation method of dissaving polymer according to claim 6, which is characterized in that carrying out dissaving polymer Preparation when, reaction temperature be 50-60 degrees Celsius；Reaction time is 1-3 hours.
9. application of the dissaving polymer as described in one of claim 1-5 in preparing wound dressing.
10. application of the dissaving polymer in preparing tissue adhesive as described in one of claim 1-5.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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