CN107899078A - A kind of method in three-dimensional rack surface covalent bonding bioactive layer - Google Patents
A kind of method in three-dimensional rack surface covalent bonding bioactive layer Download PDFInfo
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- CN107899078A CN107899078A CN201711019465.1A CN201711019465A CN107899078A CN 107899078 A CN107899078 A CN 107899078A CN 201711019465 A CN201711019465 A CN 201711019465A CN 107899078 A CN107899078 A CN 107899078A
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Abstract
The invention belongs to the technical field of organizational project, discloses a kind of method in three-dimensional rack surface covalent bonding bioactive layer.The method is：In inert atmosphere, using water as reaction medium, using the high molecular material stent containing alkynyl, the bioactive macromolecule for being modified with azido, the crosslinking agent containing alkynyl and the active small molecular of alkynyl is modified with as raw material, the reaction of azido and alkynyl occurs under the action of catalyst, so that being modified with bioactive layer on high molecular material stent, the three-dimensional rack of surface covalent bonding bioactive layer is obtained.The method reaction condition of the present invention is gentle, flexible and efficient, can realize the uniformly firm modification of three-dimensional structure material surface, three-dimensional structure form is not limited, applied widely；Bioactive layer consolidates combination with three-dimensional rack.
Description
Technical field
The invention belongs to field of tissue engineering technology, is related to a kind of in the side of three-dimensional rack surface covalent bonding bioactive layer
Method, more particularly to the firm bioactivity method of modifying on macromolecule complex three-dimensional structure stand surface.
Background technology
One of the three big key elements of tissue engineering bracket material as organizational project, it provides growth for organizational project cell
Three-dimensional environment, good environment is provided for tissue repair.Preferable stent not only needs appropriate mechanical property and degradation property,
It is also essential that higher porosity and specific surface area, which is suitable for the adhesion of cell and growth and good biocompatibility,
's.Therefore, tissue engineering bracket develops to three dimensional stress, FDM Fused Deposition Modelings technology, SLS Selective Laser Sinterings, quiet
Electrospinning and 3D printing technique instead of solvent casting method, particle leaching method, gas foaming method, fiber mesh and glue gradually
The method that the tradition such as connection, stage partition method, melt-shaping method, solution casting method and freeze-drying prepares three-dimensional rack, carries
It is high to three-dimensional rack pore size, the control of porosity and inner passage.
Tissue engineering bracket in addition to preferable structure, biocompatibility also it is particularly important that, on the one hand need avoid
Trigger inflammation or teratogenesis reaction, on the other hand the bio-carrier as cell is, it is necessary to assign material some Biofunctionals.This is just
Need the modification to timbering material progress bioactive molecule.Although the progress of three-dimensional stent material preparation method is to a certain degree
On improve the situation of cell adherence and growth, but bring some difficulty to the modification of material activity molecule.Modification side
Method includes this modifies and surface and is modified.Due to most bioactive molecules can not bear it is three-dimensionally shaped during hot environment or pole
The treatment conditions at end, most bioactive molecules are modified to surface modification.
The surface modification of tissue engineering bracket includes physical modification and chemical modification.Physical modification is i.e. by active material or band
The material of active molecule is coated by physics or bioadhesive adheres to rack surface, and one side physical modification is trained in cell
Have the shortcomings that not enough to consolidate in foster process, on the other hand for the three-dimensional rack of more complex structure, can not accomplish internal holes
The complete adhesion of gap.Chemical modification be by way of chemical bonding by bioactive molecule or with bioactive molecule material engagement arrive
The surface of three-dimensional rack.Although wherein trigger the method for bonding more firmly and square compared to physical modification by light or ray
Just, but with physical modification have the shortcomings that identical, i.e., light or ray uniformly can not be irradiated in three-dimensional rack hole without dead angle
Inside, for hole is smaller or the stent of complicated architectures for, particularly difficult therefore light-initiated chemical bonding is more applicable for
The bioactivity modification of two-dimentional base material.Repairing before being molded is more suitable for by the method chemical modification bioactive molecule of solution reaction
Decorations, and want then destroy the structure of stent to varying degrees by solution reaction after being molded.
Click chemistry (click chemistry) is 2001 by Nobel chemistry Prize winner K.Barry
The module that Sharpless is proposed first is combined to concept, it is that one kind selects the raw material that is easy to get, by modular, reliable
, efficient, high selectivity chemical transformation realize that heteroatoms connect (C-X-C), it is each with inexpensive Fast back-projection algorithm
The combinatorial chemistry new method of class noval chemical compound.The high molecular material that the present invention selects covalent bond to be modified with alkynyl is prepared into stent,
Then the characteristics of utilizing click chemistry so that in water mutually with gentle condition at interface click rapidly and efficiently occurs for three-dimensional rack
Reaction, so as to fulfill the modification of three-dimensional rack surface bioactive.In addition the aqueous phase reactions of hydrogel can ensure any structure
Three-dimensional rack inside equably modified, and this chemical modification is reliable and stable.Further, since hydrogel is flexible controllable
Property, by the species of crosslinking agent, dosage and the regulation and control of time, it might even be possible to which space and quantity to bioactive molecule carry out
Control accurate.The high molecular material for being modified with alkynyl selected at the same time can machine-shaping into constitutionally stable three-dimensional rack, tool
There is preferable mechanical property.
The content of the invention
The shortcomings that in order to overcome the prior art and deficiency, are total to it is an object of the invention to provide one kind on three-dimensional rack surface
The method of valency bonding bio active layer.The method of the present invention can realize three-dimensional structure material surface uniformly firm modification (with
Exemplified by physical absorption, when absorption environment or condition are destroyed and can cause De contamination, it is not sufficiently stable), do not have to three-dimensional structure form
Limitation, it is applied widely, it is flexible and efficient, provided for the bioactivity modification that field of tissue engineering technology complex three-dimensional structural material consolidates
May.
The purpose of the present invention is achieved through the following technical solutions：
A kind of method in three-dimensional rack surface covalent bonding bioactive layer, comprises the following steps：
In inert atmosphere, using water as reaction medium, with the high molecular material stent containing alkynyl, azido is modified with
Bioactive macromolecule, the crosslinking agent containing alkynyl are raw material with the active small molecular for being modified with alkynyl, in the effect of catalyst
The lower reaction that azido and alkynyl occurs so that be modified with bioactive layer on high molecular material stent, obtain surface covalent bond
Close the three-dimensional rack of bioactive layer.
The bioactive macromolecule for being modified with azido is that bioactive macromolecule introduces azido by modified
Compound；The crosslinking agent containing alkynyl is that crosslinking agent passes through the modified compound for introducing alkynyl；The height containing alkynyl
Molecular material stent refers to that high molecular material introduces alkynyl by modified, is subsequently processed into type into stent；It is described to be modified with alkynyl
Active small molecular be that active small molecular is prepared by the modified compound for introducing alkynyl by conventional method.Institute
It is the small peptide containing amino or carboxyl functional group or glycosyl medicine to state active small molecular.These materials can also be by buying
Arrive.
The high molecular material stent containing alkynyl is formed by the polymer material molding containing alkynyl, described to contain
The high molecular material of alkynyl is high molecular material that is water-insoluble and being modified with alkynyl, and the high molecular material containing alkynyl is excellent
Elect the polylactic acid for being modified with alkynyl, the polyglycolic acid for being modified with alkynyl as, the polyacrylic acid for being modified with alkynyl, be modified with alkynyl
Polycaprolactone is modified with one or more of polyurethane of alkynyl, the number-average molecular weight of the high molecular material containing alkynyl
30000-100000；The high molecular material containing alkynyl is that high molecular material is passed through the modified material for introducing alkynyl and being formed
Material, is prepared by conventional method.
The three-dimensionally shaped method of the high molecular material stent containing alkynyl include electrostatic spinning, 3D printing, FDM technology,
One kind in the methods of 3DP technologies；
The bioactive macromolecule for being modified with azido is to be modified with the gelatin of azido, be modified with the saturating of azido
Bright matter acid, be modified with the Sodium Hyaluronate of azido, be modified with more than one in the chitosan of azido；It is described to be modified with nitrine
The bioactive macromolecule of base is that bioactive macromolecule is passed through routine by the modified compound for introducing azido and being formed
Method be prepared.
The crosslinking agent containing alkynyl be modified with alkynyl polycaprolactone (PEG) (molecular weight is preferably 100~
1000) more than one in the polyacrylic acid (PAA) of alkynyl, are modified with；
The active small molecular for being modified with alkynyl is to be modified with the small peptide of alkynyl or be modified with the glycosyl medicine of alkynyl
More than one；The RGD that is preferably modified with alkynyl, the TGF-β 1 for being modified with alkynyl, be modified with the heptapeptide of alkynyl, be modified with alkynyl
RGDfk, be modified with the cRGDfk of alkynyl, be modified with more than one in the RGDS of alkynyl；It is described to be modified with the active small of alkynyl
Molecule is to be prepared by the modified compound for introducing alkynyl, can also pass through purchase active small molecular by conventional method
It can buy.The active small molecular is the small peptide containing amino or carboxyl functional group or glycosyl medicine.
The catalyst stand alone as copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid (sodium)/boric acid or CuBr/PMDETA,
Anhydrous cupric sulfate/sodium ascorbate；The dosage of catalyst is conventional amount used.
Alkynyl in the high molecular material containing alkynyl：It is modified with azido in the bioactive macromolecule of azido：
The molar ratio of alkynyl is 1 in crosslinking agent containing alkynyl：(1.5~5)：Mole of azido in (0.4~1) and these types of material
Integral molar quantity of the amount more than alkynyl；
The content for being modified with azido in the bioactive macromolecule of azido meets：1mol is modified with azido
Azido >=2mol in bioactive macromolecule, is preferably ＞ 2mol.
It is described to be modified with alkynyl in the active small molecular of alkynyl and be modified with nitrine in the bioactive macromolecule of azido
The molar ratio of base is (0.1~1.5)：1.
Preferably, the method in three-dimensional rack surface covalent bonding bioactive layer, concretely comprises the following steps：
(1-1) will be modified with the bioactive macromolecule of azido, the crosslinking agent containing alkynyl in inert atmosphere and water
Reacted, washed by the effect of catalyst with the high molecular material stent containing alkynyl, dry, obtaining surface bond has life
The high molecular material stent of thing active macromolecules；The crosslinking agent containing alkynyl is that the end group of bifunctionality or polyfunctionality is
The crosslinking agent of alkynyl；
(1-2) has the bioactivity big in inert atmosphere and water, by the active small molecular for being modified with alkynyl and surface bond
The high molecular material stent of molecule is reacted under the action of catalyst, is washed, dry, and it is living to obtain surface covalent bonding biology
The three-dimensional rack of property layer.
Catalyst each stands alone as copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid described in step (1-1) and (1-2)
(sodium)/boric acid or CuBr/PMDETA；The dosage of catalyst is conventional amount used；
The condition reacted described in step (1-1) and (1-2) each stands alone as 10~80 DEG C of 2~48h of reaction；The drying
Condition each stand alone as 40~70 DEG C of dry 12~24h.
Again preferably, the method in three-dimensional rack surface covalent bonding bioactive layer, concretely comprises the following steps：
(2-1) in an inert atmosphere, by the bioactive macromolecule for being modified with azido, the crosslinking agent containing alkynyl, contains
The high molecular material stent for playing the role of alkynyl and the active small molecular for being modified with alkynyl are carried out by catalyst in water jointly
Reaction, is washed, dry, obtains the three-dimensional rack of surface covalent bonding bioactive layer；The crosslinking agent containing alkynyl is double
The end group of degree of functionality or polyfunctionality is the crosslinking agent of alkynyl.
Catalyst described in step (2-1) is copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid (sodium)/boric acid or CuBr/
PMDETA；The dosage of catalyst is conventional amount used；
The condition reacted described in step (2-1) is 10~80 DEG C of 2~48h of reaction；The condition of the drying is 40~70
DEG C dry 12~24h.
Again preferably, the method in three-dimensional rack surface covalent bonding bioactive layer, concretely comprises the following steps：
(3-1) will be modified with the bioactive macromolecule of azido and the high score containing alkynyl in inert atmosphere and water
Sub- stock support is reacted by the effect of catalyst, is washed, and dry, obtaining surface bond has the height of bioactive macromolecule
Molecular material stent；The content that azido in the bioactive macromolecule of azido is modified with this step is less than containing alkynyl
The content of alkynyl in high molecular material stent；
Surface bond is had high molecular material stent, the modification of bioactive macromolecule by (3-2) in inert atmosphere and water
The bioactive macromolecule and the crosslinking agent containing alkynyl for playing the role of azido are reacted by catalyst, are washed, dry,
Obtain the high molecular material stent of surface modification；The crosslinking agent containing alkynyl is that the end group of bifunctionality or polyfunctionality is
The crosslinking agent of alkynyl；
(3-3) in inert atmosphere and water, will be modified with alkynyl active small molecular and surface be modified high molecular material
Stent is reacted under the action of catalyst, is washed, dry, obtains the three-dimensional rack of surface covalent bonding bioactive layer.
Catalyst each stands alone as copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid described in step (3-1)~(3-3)
(sodium)/boric acid or CuBr/PMDETA；The dosage of catalyst is conventional amount used；
Reacted described in step (3-1)~(3-3) and each stand alone as 10~80 DEG C of 2~48h of reaction；The condition of the drying
Each stand alone as 40~70 DEG C of dry 12~24h.
Compared with prior art, the present invention has the following advantages and beneficial effect：
(1) the processing of high molecular material shaping of the invention that covalent bond is modified with to alkynyl is prepared into constitutionally stable three-dimensional branch
Frame, then by the reaction of azido and alkynyl in three-dimensional stent material surface covalent bonding bioactive layer so that biology is living
Property layer is uniformly firmly modified in three-dimensional rack, and this chemical modification is reliable and stable；And by being chemically bonded the activity of modification
Molecule is more solid and reliable in cell culture processing procedure；
(2) present invention reacts in water phase, and the aqueous phase reactions of hydrogel can realize the uniform of three-dimensional structure surfaces externally and internally
Modification, does not limit three dimensional scaffold structure complexity；
(3) species to crosslinking agent, dosage are passed through due to the flexible controllability of hydrogel (bioactive layer) in the present invention
And the regulation and control of time, it might even be possible to which space and quantity to bioactive molecule carry out control accurate, it is possible to achieve are accurately positioned
And patterning schemes；
(4) reaction condition of the invention is gentle, efficient, and click chemistry species is various, and applied widely, flexibility is strong.
Brief description of the drawings
Fig. 1 is Raman (Raman) collection of illustrative plates of the polyurethane three-dimensional stent material containing alkynyl in embodiment 1；
Fig. 2 is Raman (Raman) spectrum of the polyurethane three-dimensional rack that surface bond has chitosan gel rubber layer in embodiment 1
Figure；
Fig. 3 is the water contact angle optical picture of the polyurethane three-dimensional rack containing alkynyl in embodiment 2；Upper figure and figure below are branch
The contact angle optical picture that diverse location measures on frame；
Fig. 4 is the water contact angle optical picture of the polyurethane three-dimensional rack that surface bond has PEG gel layers in embodiment 2；On
The contact angle optical picture that figure and figure below measure for diverse location on stent.
Embodiment
With reference to embodiment and attached drawing, the present invention is described in further detail, but embodiments of the present invention are not
It is limited to this.The content that azido in the bioactive macromolecule of azido is modified with described in each embodiment meets：1mol is modified
There is azido >=2mol in the bioactive macromolecule of azido.
Embodiment 1
(1) polyurethane (Mn=35000) containing alkynyl is subjected to 3 D-printing (T=205 DEG C of P=3.5bar), average hole
Footpath size is 1200 μm, quality 0.5g (alkynyl content 0.68-1.02mmol/g PTMG, data are got by nuclear-magnetism peak area ratio,
Polyurethane of the 0.5g containing alkynyl contains 0.5mmol alkynyls), obtain the polyurethane three-dimensional rack containing alkynyl；
(2) shell that 0.5g polyurethane three-dimensional rack (1eq) (containing 0.5mmol alkynyls), 0.5g are modified with to azido gathers
The PEG200 that sugared (2eq) (azido that the chitosan of 0.5g modification azidos contains about 1mmol) and 0.63g contain alkynyl
(0.5eq) (alkynyl content is 0.4mmol/g, and the content of alkynyl is 0.4mmol in the PEG200 that 1g contains alkynyl) is added to
In 20ml water, lead to nitrogen deoxygenation 30min, weigh 0.003g copper powders and be added in reaction system, the lower 50 DEG C of reactions 6h of nitrogen protection,
Three-dimensional rack is taken out from reaction solution, EDTA/ ethanol (V/V=1:1) washing removes copper powder and unreacted small molecule, vacuum
Being dried to obtain surface bond has the polyurethane three-dimensional rack of chitosan gel rubber layer；
(3) there are polyurethane three-dimensional rack, the 500mg of chitosan gel rubber layer alkynyl-modified surface bond in step (2)
(producer buys RGDfk：RGDfk alkynyl-modified Karebay Biochem, Inc, 500mg about contains 0.5mmol alkynyls)
(1eq) is added in 20mL water, leads to nitrogen deoxygenation 30min, adds cupric sulfate pentahydrate 0.005g (0.4eq) and sodium ascorbate
0.01g (1eq), reacts 13h at 40 DEG C, and three-dimensional rack is taken out from reaction solution, EDTA/ ethanol (V/V=1:1) washing removes
Copper ion and unreacted material are removed, vacuum drying (dry temperature is 40 DEG C), the shell that obtaining surface has RGDfk modifications gathers
The polyurethane three-dimensional rack of sugared bioactive layer.
The preparation method of the polyurethane containing alkynyl is：PTMG2000 is vacuumized into 2h at 110 DEG C, is then down to room
Temperature；Precise is down to the PTMG2000 (1eq) of room temperature, and 0.5h is vacuumized at 75 DEG C, then adds the anhydrous DMAc of 20ml, stirs
HDI (2eq) and 0.5% (wt%) tin dilaurate, two isobutyl tin catalyst are added after mixing uniformly, under nitrogen protection 75 DEG C of reactions
4h, obtains polyurethane prepolymer；Chain extender containing alkynyl DPPD (2,2- propinyls -1,3- the third two is added into polyurethane prepolymer
Alcohol) (1eq), temperature is risen into 80 DEG C of reaction 4h, 90 DEG C of curing 2h is continuously heating to, it is anti-at 90 DEG C to be eventually adding excess ethyl alcohol
1h is answered, the reaction was complete by unreacted isocyanates；Methanol coprecipitated product is used after reaction, in 60 DEG C of heated-air circulation ovens
60 DEG C of dry 12h in vacuum drying chamber are transferred to after middle drying 12h and further remove solvent, obtain the polyurethane containing alkynyl.
The preparation method of the chitosan for being modified with azido：1g chitosans are dissolved in 50ml acetic acid solutions
In (2wt.%), pH value is adjusted to 5-7, bromo- 2 methylpropanoic acids of 1g2- and 2.3gEDC is added, 24h is stirred at room temperature, dialyses and freezes
It is dry, obtain reaction product；Then reaction product is dissolved in acetic acid solution (2wt.%), adjusts pH value to be added after neutrality
0.6gNaN3, 24h is reacted at room temperature, dialysis, is freeze-dried 3 days, obtains being modified with the chitosan of nitrine.
PEG (1.5mmol) is is dissolved in 25mlCH2Cl2 by the preparation method of the PEG200 containing alkynyl, Ran Houyi
Secondary addition 4- pentinoic acids (2.25mmol) and DMAP (1.5mmol), it is after stirring five minutes at room temperature, DCC (2.25mmol) is molten
Solution is in 15mlCH2Cl2, and be added in reaction solution, it is stirred overnight, filters at room temperature, concentrate, product is pure by silica gel column chromatography
Change, and use CH2Cl2/MeOH(10:1) elute；Finally, the PEG concentrate solutions containing alkynyl are precipitated and filtered in ether, obtained
To the PEG200 containing alkynyl, Mn=240；Alkynyl content about 0.4mmol/g in PEG200 containing alkynyl.
The Raman spectrogram of the polyurethane three-dimensional rack containing alkynyl of the present embodiment is as shown in Figure 1, surface bond has shell to gather
The Raman spectrogram of the polyurethane three-dimensional rack of sugared gel layer is as shown in Figure 2；Fig. 1 is that the polyurethane containing alkynyl is three-dimensional in embodiment 1
Raman (Raman) collection of illustrative plates of timbering material；Fig. 2 is that surface bond has the three-dimensional branch of the polyurethane of chitosan gel rubber layer in embodiment 1
Raman (Raman) spectrogram of frame.From Fig. 1 and 2 as can be seen that 1,2118cm-1Place alkynyl peak disappears substantially, shows that click-reaction is sent out
Raw and efficiency is very high, and the chitosan for being modified with azido is successfully bonded to the polyurethane three-dimensional rack surface containing alkynyl.
Embodiment 2
(1) polyurethane (Mn=70000) containing alkynyl is subjected to 3 D-printing (T=205 DEG C of P=3.5bar), average hole
Footpath size is 800 μm, and quality 0.8g (alkynyl content 0.68-1.02mmol/g PCL, data are got by nuclear-magnetism peak area ratio), obtains
To the polyurethane three-dimensional rack containing alkynyl；
(2) by 0.8g polyurethane three-dimensional rack (1eq) (0.8g polyurethane three-dimensional racks contain 0.8mmol alkynyls), 1.8g
It is modified with the PEG2000 (2eq) (azido that the PEG2000 of 1.8g modification azidos contains 1.6mmol) and 0.4g of azido
PAA (0.5eq) (content of alkynyl is 0.4mmol) containing alkynyl is added in 10ml water, leads to nitrogen deoxygenation 30min；Weigh
0.002gCuBr/0.002gPMDETA (0.01eq/0.1eq) is dissolved in 0.3ml anaerobic waters, its aqueous solution is added to reaction
In system, the lower 30 DEG C of reactions 10h of nitrogen protection, polyurethane three-dimensional rack is taken out from reaction solution, methanol/water (V/V=1:1)
Washing removes copper ion and unreacted small molecule, and vacuum drying, obtaining surface bond has the three-dimensional branch of the polyurethane of PEG gel layers
Frame；
(3) there are polyurethane three-dimensional rack, the 250mg of PEG gel layers alkynyl-modified the surface bond obtained in step (2)
RGDS (producer buy：RGDS alkynyl-modified Karebay Biochem, Inc, 250mg about contains 0.6mmol alkynyls)
(0.8eq) is added in 15mL water, leads to nitrogen deoxygenation 30min, adds cupric sulfate pentahydrate 0.005g (0.5eq) and sodium ascorbate
0.01g (1eq), reacts 6h at 50 DEG C, and polyurethane three-dimensional rack is taken out from reaction solution, EDTA/ ethanol (V/V=1:1)
Washing removes copper ion and unreacted material, vacuum drying, the polyurethane of PEG bioactive layer of the acquisition with RGDS modifications
Three-dimensional rack.
The preparation method of the polyurethane containing alkynyl：PCL2000 is vacuumized into 2h at 110 DEG C, is then down to room temperature；
Precise PCL2000 (1eq), vacuumizes 0.5h at 75 DEG C, then adds the anhydrous DMAc of 20ml, is stirring evenly and then adding into
Two isobutyl tin catalyst of MDI (2eq) and 0.5% (wt%) tin dilaurate, 75 DEG C of reaction 4h, obtain polyurethane under nitrogen protection
Prepolymer；The DPPD of chain extender containing alkynyl (2,2-propynyl -1,3-PD) (1eq) is added into polyurethane prepolymer, by temperature
Degree rises to 80 DEG C of reaction 4h, is continuously heating to 90 DEG C of curing 2h, is eventually adding excess ethyl alcohol and reacts 1h at 90 DEG C, by unreacted
Isocyanates the reaction was complete；Methanol coprecipitated product is used after reaction, is turned after 12h is dried in 60 DEG C of heated-air circulation ovens
Move on to 60 DEG C of dry 12h in vacuum drying chamber and further remove solvent, obtain the polyurethane containing alkynyl.
The preparation method of the PEG2000 for being modified with azido is by PEG (2mmol-OH) azeotropic distillation in toluene
And it is dissolved in 15mlTHF；The 4- toluene sulfochlorides (20mmol) being dissolved in 10mlTHF are added dropwise in 10min dropwise, room temperature is anti-
Answer 24h；Then saturation NaHCO is added3Aqueous solution, is stirred for 4h, with 50mlDCM extractions three times, merges organic phase, by merging
Organic phase is precipitated with ether, obtains PEG-OTs；Afterwards again with being dissolved in the NaN of 10mlDMF3(23mmol) is mixed, and is stirred at 30 DEG C
24h is mixed, adds the DCM of 100ml, then with salt water washing 3 times, cools down and is simultaneously precipitated from cold diethyl ether, obtain being modified with folded
The PEG2000 of nitrogen base, the content of azido is 0.9mmol/g.
The preparation method of the PAA containing alkynyl is：By acrylic acid (0.932g), acrylic acid -3- chloropropyl esters
(0.236g) and RAFT reagents (0.018g) (dodecyl -1- phenylethyl carbonic acid dithioester) are with 300：30：1 mole
Than mixing, 60 DEG C of constant temperature oil baths heat 3h, obtain mixture；By mixture and propargyl amine (0.1eq) in 1- [3 '-(dimethyl
Amino) propyl group] it is stirred overnight (12h) in -3- ethyl carbimide iodites (0.15%eq), dialyse 7 days, freeze-drying,
Obtain the PAA containing alkynyl.
The water contact angle optical picture of the polyurethane three-dimensional rack containing alkynyl is as shown in Figure 3 in the present embodiment；Surface bond
There is the water contact angle optical picture of the polyurethane three-dimensional rack of PEG gel layers as shown in Figure 4.Fig. 3 is to contain alkynyl in embodiment 2
The water contact angle optical picture of polyurethane three-dimensional rack；Fig. 4 is the polyurethane three-dimensional that surface bond has PEG gel layers in embodiment 2
The water contact angle optical picture of stent.From Fig. 3 and 4 as can be seen that comparison diagram 3, contact angle is obviously reduced, and illustrates to be modified with azido
PEG be successfully bonded to the polyurethane three-dimensional rack surface containing alkynyl.
Embodiment 3
(1) by the polyacrylic acid containing alkynyl, (producer buys：Karebay Biochem, Inc, alkynyl concentration 1mmol/g)
(Mn=65800) carrying out electrostatic spinning, (hexafluoroisopropanol is solvent, is 6% in concentration of dope, voltage 12kV, injects speed
Spend for 1ml/h, pole span 10cm), average pore size is 400 μm, quality 1g (alkynyls in the polyacrylic acid containing alkynyl of 1g
Mole is 1mmol), obtain polyacrylic acid three-dimensional rack；
(2) polyacrylic acid three-dimensional rack (1eq), the 1.5g of 1g are modified with to gelatin (the 1.5g modification azidos of azido
Gelatin in azido content be more than 2mmol/g) (content of azido is by the PEG300 of (2eq) and 1.26g alkynyl functionalization
0.38mmol/g) (0.5eq) is added in 30ml water, leads to nitrogen deoxygenation 40min, adds cupric sulfate pentahydrate 0.008g (0.2eq)
With sodium ascorbate 0.03 (1eq), the lower 10 DEG C of reactions 36h of nitrogen protection, three-dimensional rack is taken out from reaction solution, EDTA/ second
Alcohol (V/V=1:1) washing removes copper ion and unreacted small molecule, and vacuum drying, obtaining surface bond has gelatin gel layer
Polyacrylic acid three-dimensional rack；
(3) surface bond obtained in step (2) is had to polyacrylic acid three-dimensional rack, the 250mg alkynyls of gelatin gel layer
(producer buys the RGDS of modification：RGDS alkynyl-modified Karebay Biochem, Inc, 250mg contains the alkynes of 0.45mmol
Base) (0.5eq) is added in 20mL water, lead to nitrogen deoxygenation 40min；By 0.002gCuBr/0.002gPMDETA (0.01eq/
0.1eq) it is dissolved in 0.3ml anaerobic waters, its aqueous solution is added in reaction system, the lower 40 DEG C of reactions 8h of nitrogen protection will
Three-dimensional rack takes out from reaction solution, EDTA/ ethanol (V/V=1:1) washing removes copper ion and unreacted small molecule, vacuum
Dry (dry temperature is 40 DEG C), obtains the polyacrylic acid three-dimensional rack of the gelatin bioactive layer with RGDS modifications.
The preparation method of the gelatin for being modified with azido is：By 1g Gelatins in 50ml water, pH value is adjusted
To 5-7, add bromo- 2 methylpropanoic acids of 1g2- and 24h is stirred at room temperature in 2.3gEDC, solution, dialyse and be freeze-dried, obtain product；
Then it is product is soluble in water, add 0.6gNaN3, 24h is reacted at room temperature, dialysis, is freeze-dried 3 days, obtains Azide gelatin.
PEG (1.5mmol) is is dissolved in 25mlCH2Cl2 by the preparation method of the PEG300 containing alkynyl, Ran Houyi
Secondary addition 4- pentinoic acids (2.5mmol) and DMAP (1.5mmol), after stirring five minutes at room temperature, DCC (2.25mmol) is dissolved
In 15mlCH2Cl2, and it is added in reaction solution, is stirred overnight at room temperature, filter, concentrate, product is pure by silica gel column chromatography
Change, and with CH2Cl2/MeOH (10:1) elute；Finally, the PEG concentrate solutions containing alkynyl are precipitated and filtered in ether,
Obtain the PEG300 containing alkynyl；Alkynyl content about 0.38mmol/g in PEG300 containing alkynyl.
Embodiment 4
(1) by the PLA containing alkynyl, (producer buys：Karebay Biochem, Inc, the content of alkynyl is 0.5mmol/g)
(Mn=54000) 3 D-printing (T=205 DEG C of P=3.5bar) is carried out, average pore size is 1000 μm, obtains the three-dimensional branch of polylactic acid
Frame, quality 2g；
(2) by 2g three-dimensional racks (1eq) (mole of alkynyl is 1mmol in the PLA containing alkynyl of 2g), 1g azidos
Gelatin (azido content is more than 2mmol/g in the gelatin of 1g azidos) (2eq), 1.5g contain the PEG200 of alkynyl, and (alkynyl contains
Measure as 0.4mmol/g) (0.6eq) and 350mg modification alkynyl cRGDfk (producer buy：Karebay Biochem, Inc,
The alkynyl that the cRGDfk of 350mg alkynyl functionalization contains 0.7mmol) (1eq) is added in 25ml water, lead to nitrogen deoxygenation 30min,
Add cupric sulfate pentahydrate 0.008g (0.2eq) and sodium ascorbate 0.03 (1eq), the lower 30 DEG C of reactions 12h of nitrogen protection, by three-dimensional
Stent takes out from reaction solution, EDTA/ ethanol (V/V=1:1) washing removes copper ion and unreacted small molecule, vacuum are done
It is dry, obtain the PLA three-dimensional racks of the gelatin bioactive layer with cRGDfk modifications.
The preparation method of the gelatin for being modified with azido is：By 1g Gelatins in 50ml water, pH value is adjusted
To 5-7, add bromo- 2 methylpropanoic acids of 1g2- and 24h is stirred at room temperature in 2.3gEDC, solution, dialyse and be freeze-dried, obtain product；
Then it is product is soluble in water, add 0.6gNaN3, 24h is reacted at room temperature, dialysis, is freeze-dried 3 days, obtains Azide gelatin.
The preparation method of the PEG200 containing alkynyl is by PEG (Mn：1.5mmol) it is dissolved in 25mlCH2Cl2, so
After sequentially add 4- pentinoic acids (2.25mmol) and DMAP (1.5mmol), at room temperature stir five minutes after, by DCC
(2.25mmol) is dissolved in 15mlCH2Cl2, and is added in reaction solution, is stirred overnight at room temperature, filters, and concentration, product passes through
Silica gel chromatography, and with CH2Cl2/MeOH (10:1) elute；Finally, by the PEG concentrate solutions containing alkynyl in ether
Precipitate and filter, obtain the PEG200 containing alkynyl, Mn=240；Alkynyl content about 0.4mmol/ in PEG200 containing alkynyl
g。
Embodiment 5
(1) polyurethane (Mn=50000) containing alkynyl is subjected to 3 D-printing (T=205 DEG C of P=3.5bar), average hole
Footpath size is 500 μm, quality 1g (mole of alkynyl is 1mmol in the polyurethane containing alkynyl of 1g), obtains polyurethane three-dimensional
Stent；
(2) 1g three-dimensional racks (1eq) and 0.9g are modified with the PEG2000 of azido (content of azido is
0.9mmol/g) (1eq) is added in 10ml water, is led to nitrogen deoxygenation 30min, is weighed 0.002gCuBr/0.002gPMDETA
(0.01eq/0.1eq) is dissolved in 0.3ml anaerobic waters, its aqueous solution is added in reaction system, and lower 30 DEG C of nitrogen protection is anti-
24h is answered, three-dimensional rack is taken out from reaction solution, methanol/water (V/V=1:1) washing removes copper ion and small point unreacted
Son, is dried in vacuo, and obtains being bonded with the polyurethane three-dimensional rack of PEG；
(3) the polyurethane three-dimensional rack, the 0.9g that are bonded with PEG that are obtained in step (2) are modified with azido
The PEG300 (end group is alkynyl, and the content of alkynyl is 0.38mmol/g) (0.5eq) that PEG2000 (1eq), 1.26g contain alkynyl
It is added in 20mL water, leads to nitrogen deoxygenation 30min, adds cupric sulfate pentahydrate 0.005g (0.5eq) and sodium ascorbate 0.01
(1eq), reacts 10min at 50 DEG C, and three-dimensional rack is taken out from reaction solution, EDTA/ ethanol (V/V=1:1) washing removes
Copper ion and unreacted small molecule, vacuum drying, obtaining surface bond has the polyurethane three-dimensional rack of PEG gel layers；
(4) there are polyurethane three-dimensional rack, the 400mg of PEG gel layers alkynyl-modified the surface bond obtained in step (3)
TGF-β 1 (producer buy：Alkynes of the TGF-β 1 containing 0.8mmol of Karebay Biochem, Inc, 400mg alkynyl functionalization
Base) (0.8eq) is added in 20mL water, leads to nitrogen deoxygenation 30min, add cupric sulfate pentahydrate 0.005g (0.5eq) and Vitamin C
Sour sodium 0.01 (1eq), reacts 6h at 50 DEG C, and three-dimensional rack is taken out from reaction solution, EDTA/ ethanol (V/V=1:1) wash
Remove copper ion and unreacted small molecule, vacuum drying, the polyurethane for the PEG bioactive layers that acquisition is modified with TGF-β 1
Three-dimensional rack.
The preparation method of the polyurethane containing alkynyl：PCL2000 is vacuumized into 2h at 110 DEG C, is then down to room temperature；
Precise PCL2000 (1eq), vacuumizes 0.5h at 75 DEG C, then adds the anhydrous DMAc of 20ml, is stirring evenly and then adding into
Two isobutyl tin catalyst of MDI (2eq) and 0.5% (wt%) tin dilaurate, 75 DEG C of reaction 4h, obtain polyurethane under nitrogen protection
Prepolymer；The DPPD of chain extender containing alkynyl (2,2-propynyl -1,3-PD) (1eq) is added into polyurethane prepolymer, by temperature
Degree rises to 80 DEG C of reaction 4h, is continuously heating to 90 DEG C of curing 2h, is eventually adding excess ethyl alcohol and reacts 1h at 90 DEG C, by unreacted
Isocyanates the reaction was complete；Methanol coprecipitated product is used after reaction, is turned after 12h is dried in 60 DEG C of heated-air circulation ovens
Move on to 60 DEG C of dry 12h in vacuum drying chamber and further remove solvent, obtain the polyurethane containing alkynyl.
The preparation method of the PEG2000 for being modified with azido is by PEG (2mmol-OH) azeotropic distillation in toluene
And it is dissolved in 15mlTHF；The 4- toluene sulfochlorides (20mmol) being dissolved in 10mlTHF are added dropwise in 10min dropwise, room temperature is anti-
Answer 24h；Then saturation NaHCO is added3Aqueous solution, is stirred for 4h, with 50mlDCM extractions three times, merges organic phase, by merging
Organic phase is precipitated with ether, obtains PEG-OTs；Afterwards again with being dissolved in the NaN of 10mlDMF3(23mmol) is mixed, and is stirred at 30 DEG C
24h is mixed, adds the DCM of 100ml, then with salt water washing 3 times, cools down and is simultaneously precipitated from cold diethyl ether, obtain being modified with folded
The PEG2000 of nitrogen base, the content of azido is 0.9mmol/g.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention and from the limit of embodiment
System, all raw materials and formula can make adjustment in the case where the theoretical foundation that can carry out click-reaction and synthetic hydrogel instructs,
It is related to click-reaction type, including the reaction of cycloaddition reaction, nucleophilic ring opening, the addition of the carbonylation of non-alcohol aldehyde, carbon carbon multikey
Reaction etc.；Click order；Click on direction；Catalytic type, including cuprous catalysis, without copper catalysis；Catalyst system and catalyzing includes copper wire, copper
Powder, cupric sulfate pentahydrate/ascorbic acid (sodium)/boric acid or CuBr/PMDET；Hydrogel monomer species；Three-dimensional stent material species,
Forming method；Bioactive molecule species；And the method for modifying of functional group.Other any Spirit Essences without departing from the present invention
With made under principle change, modification, replacement, combine, simplification, should be equivalent substitute mode, be included in the present invention's
Within protection domain.
Claims (10)
- A kind of 1. method in three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：Comprise the following steps：In inert atmosphere, using water as reaction medium, with the high molecular material stent containing alkynyl, the biology of azido is modified with Active macromolecules, the crosslinking agent containing alkynyl are raw material with the active small molecular for being modified with alkynyl, are sent out under the action of catalyst The reaction of raw azido and alkynyl so that be modified with bioactive layer on high molecular material stent, obtain surface covalent bond symphysis The three-dimensional rack of thing active layer.
- 2. according to claim 1 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：It is described High molecular material stent containing alkynyl is formed by the polymer material molding containing alkynyl, the macromolecule containing alkynyl Material is to be modified with the polylactic acid of alkynyl, the polyacrylic acid for being modified with the polyglycolic acid of alkynyl, being modified with alkynyl, be modified with alkynyl Polycaprolactone or be modified with one or more of polyurethane of alkynyl, the number-average molecular weight of the high molecular material containing alkynyl 30000-100000；The bioactive macromolecule for being modified with azido is the gelatin for being modified with azido, the hyalomitome for being modified with azido Acid, be modified with the Sodium Hyaluronate of azido, be modified with more than one in the chitosan of azido；The crosslinking agent containing alkynyl be modified with the polycaprolactone of alkynyl, be modified with the polyacrylic acid of alkynyl one kind with On；The active small molecular for being modified with alkynyl is to be modified with the small peptide of alkynyl or be modified with the glycosyl medicine of alkynyl a kind of More than.
- 3. according to claim 2 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：It is described The active small molecular for being modified with alkynyl be modified with the RGD of alkynyl, the heptapeptide for being modified with the TGF-β 1 of alkynyl, being modified with alkynyl, The RGDfk that is modified with alkynyl, the cRGDfk for being modified with alkynyl, be modified with more than one in the RGDS of alkynyl.
- 4. according to claim 1 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：It is described Catalyst stands alone as copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid (sodium)/boric acid or CuBr/PMDETA；Alkynyl in the high molecular material containing alkynyl：It is modified with azido in the bioactive macromolecule of azido：Contain The molar ratio of alkynyl is 1 in the crosslinking agent of alkynyl：(1.5~5)：The mole of azido is big in (0.4~1) and these types of material In the integral molar quantity of alkynyl；It is described to be modified with alkynyl in the active small molecular of alkynyl and be modified with azido in the bioactive macromolecule of azido Molar ratio is (0.1~1.5)：1.
- 5. according to claim 1 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：Specifically Step is：(1-1) will be modified with the bioactive macromolecule of azido, the crosslinking agent containing alkynyl with containing in inert atmosphere and water The high molecular material stent for playing the role of alkynyl is reacted by catalyst, is washed, and dry, obtaining surface bond has biological work The high molecular material stent of property macromolecular；The crosslinking agent containing alkynyl is that the end group of bifunctionality or polyfunctionality is alkynyl Crosslinking agent；(1-2) has bioactive macromolecule in inert atmosphere and water, by the active small molecular for being modified with alkynyl and surface bond High molecular material stent reacted under the action of catalyst, wash, it is dry, obtain surface covalent bonding bioactive layer Three-dimensional rack.
- 6. according to claim 5 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：Step Catalyst described in (1-1) and (1-2) each stand alone as copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid (sodium)/boric acid or CuBr/PMDETA；The condition reacted described in step (1-1) and (1-2) each stands alone as 10~80 DEG C of 2~48h of reaction；The bar of the drying Part each stands alone as 40~70 DEG C of dry 12~24h.
- 7. according to claim 1 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：Specifically Step is：(2-1) in an inert atmosphere, by the bioactive macromolecule for being modified with azido, the crosslinking agent containing alkynyl, contains alkynes The high molecular material stent of base is reacted by the effect of catalyst in water jointly with being modified with the active small molecular of alkynyl, Washing, it is dry, obtain the three-dimensional rack of surface covalent bonding bioactive layer；The crosslinking agent containing alkynyl is bifunctionality Or the crosslinking agent that the end group of polyfunctionality is alkynyl.
- 8. according to claim 7 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：Step Catalyst described in (2-1) is copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid (sodium)/boric acid or CuBr/PMDETA；The condition reacted described in step (2-1) is 10~80 DEG C of 2~48h of reaction；The condition of the drying is dry for 40~70 DEG C Dry 12~24h.
- 9. according to claim 1 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：Specifically Step is：(3-1) will be modified with the bioactive macromolecule of azido and the macromolecule material containing alkynyl in inert atmosphere and water Material stent is reacted by the effect of catalyst, is washed, and dry, obtaining surface bond has the macromolecule of bioactive macromolecule Stock support；The content that azido in the bioactive macromolecule of azido is modified with this step is less than the high score containing alkynyl The content of alkynyl in sub- stock support；(3-2) in inert atmosphere and water, by surface bond have the high molecular material stent of bioactive macromolecule, be modified with it is folded The bioactive macromolecule of nitrogen base is reacted with the crosslinking agent containing alkynyl by the effect of catalyst, is washed, dry, is obtained The high molecular material stent that surface is modified；The crosslinking agent containing alkynyl is that the end group of bifunctionality or polyfunctionality is alkynyl Crosslinking agent；(3-3) in inert atmosphere and water, will be modified with alkynyl active small molecular and surface be modified high molecular material stent Reacted, washed under the action of catalyst, it is dry, obtain the three-dimensional rack of surface covalent bonding bioactive layer.
- 10. according to claim 9 in the method for three-dimensional rack surface covalent bonding bioactive layer, it is characterised in that：Step Suddenly catalyst described in (3-1)~(3-3) each stand alone as copper wire, copper powder, cupric sulfate pentahydrate/ascorbic acid (sodium)/boric acid or CuBr/PMDETA；Reacted described in step (3-1)~(3-3) and each stand alone as 10~80 DEG C of 2~48h of reaction；The condition of the drying is each Stand alone as 40~70 DEG C of dry 12~24h.
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Application publication date: 20180413 |