CN107050510A - A kind of sodium alginate/glutin injectable double-network hydrogel and its preparation and application - Google Patents

A kind of sodium alginate/glutin injectable double-network hydrogel and its preparation and application Download PDF

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CN107050510A
CN107050510A CN201710447755.XA CN201710447755A CN107050510A CN 107050510 A CN107050510 A CN 107050510A CN 201710447755 A CN201710447755 A CN 201710447755A CN 107050510 A CN107050510 A CN 107050510A
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sodium alginate
glutin
preparation
gelatin
network hydrogel
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莫秀梅
袁柳
韩林颖俊
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Donghua University
National Dong Hwa University
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Abstract

The present invention relates to a kind of sodium alginate/glutin injectable double-network hydrogel and its preparation and application, hydrogel raw material includes：The aldehyde sodium alginate and amination gelatin of esterification.Prepare：The esterification aldehyde sodium alginate aqueous solution is mixed with the aqueous solution of amination gelatin, is crosslinked at 37 DEG C after 5 15min, then carries out ultraviolet irradiation crosslinking, is produced.Selected sodium alginate and gelatin are natural biologic materials in the present invention, and mixing, which spontaneous can be cross-linked to form after the first layer network, illumination, after modified forms the second layer network.Prepared double-network hydrogel is nontoxic, tasteless, biodegradable, and cheap, safe and reliable with good biocompatibility and mechanical performance, with low cost, preparation method is simple.

Description

A kind of sodium alginate/glutin injectable double-network hydrogel and its preparation and application
Technical field
The invention belongs to hydrogel material and its preparation and application field, more particularly to a kind of sodium alginate/glutin can be noted Penetrate double-network hydrogel and its preparation and application.
Background technology
Tissue, the damage of organ, dysfunction or forfeiture are one of major health harm of facing mankind, are also to cause people Class disease and dead main reason, the appearance of organizational project bring new solution for this global problem.Make For an emerging interdisciplinary fields, organizational project is related to cell biology, molecular biology, material science, clinical medicine, life The subjects such as thing engineering, by the way that cell biology and materialogy are combined, build tissue or organ, most in vitro or in vivo The problems such as whole fundamentally missing of solution tissue and organ.
Hydrogel is a kind of macromolecule network of the high degree of water formed by physically or chemically crosslinked action, since 1960 Year by Wichterle et al. first by the use of hydrogel as contact lenses after, hydrogel is widely studied applied to biomedical Field.Particularly received more and more attention nearly ten years with the research of organizational project, hydrogel due to its high degree of water, Physical property is similar to the characteristic of extracellular matrix (ECM), by wide as three-dimensional tissue's engineering rack that sertoli cell grows General research.
As the improvement of people's living standards, to medical procedure it is painless, without scar, operation easily require more and more higher, Therefore injection aquagel can realize painless non-invasive procedures as a kind of new fast treating means, be even more by increasingly Many attention is simultaneously gradually favored, one of important directions as future biological medical material application development for people.
Photopolymerization is also widely used as a kind of new polymerization methodses in organizational project, and traditional polymerization It is many compared to advantage：It can carry out at ambient and physiological conditions, curing rate is fast (from less than one second to a few minutes)；Reaction is put The heat gone out is few；Reaction condition is gentle, and damage will not be caused to cell and tissue；Polymer precursor can be made water-soluble by photopolymerization Liquid is formed in situ hydrogel, so can be used to prepare injection aquagel.
The content of the invention
The technical problems to be solved by the invention be to provide a kind of sodium alginate/glutin injectable double-network hydrogel and its Prepare and apply, sodium alginate/glutin injectable double-network hydrogel of the invention can be used for organizational project, the original of the hydrogel Material selection sodium alginate and gelatin, cheap, good biocompatibility can be absorbed by organism and degrade；Preparation method is simple, Implementation condition is gentle, and the hydrogel good biocompatibility, mechanical performance is excellent.
A kind of sodium alginate/glutin injectable double-network hydrogel of the present invention, the hydrogel raw material includes：Esterification Aldehyde sodium alginate and amination gelatin, wherein the aldehyde sodium alginate and the mass ratio of amination gelatin that are esterified be 0.75~ 1.5:1。
A kind of preparation method of sodium alginate/glutin injectable double-network hydrogel of the present invention, including：
The esterification aldehyde sodium alginate aqueous solution is mixed with the aqueous solution of amination gelatin, 5-15min is crosslinked at 37 DEG C Afterwards, then ultraviolet irradiation crosslinking is carried out, produces sodium alginate/glutin injectable double-network hydrogel.
The aqueous solution of the esterification aldehyde sodium alginate aqueous solution and amination gelatin is 1 by volume:1 mixing.
The aqueous solution of esterification the aldehyde sodium alginate aqueous solution and amination gelatin is mixed into：Two kinds of solution are by two notes Emitter is expelled in same syringe needle and mixed simultaneously.
The quality concentration of volume percent of the esterification aldehyde sodium alginate aqueous solution is 20%-30%；Amination gelatin The quality concentration of volume percent of the aqueous solution is 20%.
It is described esterification aldehyde sodium alginate preparation be specially：(1) under the conditions of room temperature lucifuge, the sodium metaperiodate aqueous solution is added Enter into the aqueous solution of sodium alginate, react 4~6h, dialyse, freeze-drying obtains aldehyde radical sodium alginate；Its meso-periodic acid The molar ratio of sodium and sodium alginate is 0.88~1：1；(2) in the ethyl sulfonic acid Mes buffer solutions of aldehyde radical sodium alginate, add Carbodiimides and HOSu NHS, lucifuge activation 30-45min, is subsequently added methacrylic acid -2- amino second at room temperature React and stay overnight under the conditions of base ester hydrochloride, room temperature lucifuge, dialyse, freeze-drying obtains being esterified aldehyde sodium alginate；Wherein aldehyde radical The mol ratio of carboxyl, carbodiimides, HOSu NHS and methacrylic acid -2- amino-ethyl esters on change sodium alginate For 3：3：1：1.5.
Sodium alginate is middle viscosity 580mpa.s sodium alginates in the step (1), and weight average molecular weight is about 1,440,000, G embedding Section ratio is 40%.
Dialysed in the step (2)：Bag filter molecular cut off is 14000Da, and the time of dialysis is 2~3 days.
Freeze-drying is then placed in vacuum freeze drier and frozen first to freeze 6h at -80 DEG C in the step (2) It is dry.
The preparation method of the amination gelatin includes：Ethylenediamine is added in aqueous gelatin solution, pH is to 5.0 for regulation, Water-soluble carbodiimide EDC, 37 DEG C of 4~6h of reaction are added, are dialysed, freeze-drying obtains amination gelatin；Wherein gelatin and second The mol ratio of diamines is 1：1；Gelatin is 1 with water-soluble carbodiimide mol ratio：2.
The gelatin is Bos taurus domesticus Gmelin, and jelly force intensity is 150~180g, and viscosity 3.5~4.3, weight average molecular weight is about 3.7 Ten thousand.
Dialysis in the preparation method of above-mentioned amination gelatin is：Bag filter molecular cut off be 3500Da, dialysis when Between be 2~3 days；It is freeze-dried and freezes 6h at -80 DEG C for elder generation, is then placed in vacuum freeze drier and is freezed.
The ultraviolet generator used in ultraviolet irradiation crosslinking is wavelength 365nm, power 5mw/cm2Uviol lamp, ultraviolet photograph Penetrate 10~15min of crosslinking.
Light trigger is used in ultraviolet irradiation crosslinking, the final mass volume basis of the light trigger of use in system is dense Spend for 0.1%, preferred photoinitiator be 2- hydroxy-2-methyls -1- [4- (2- hydroxyl-oxethyls) phenyl] -1- acetone (I2959, Sigma companies, Shanghai, China).
A kind of application of sodium alginate/glutin injectable double-network hydrogel of the present invention, it is characterised in that：Alginic acid Sodium/gelatin injectable double-network hydrogel is applied to the photo-crosslinking injection aquagel support in organizational project.
The preparation method for the sodium alginate/glutin injectable double-network hydrogel available for organizational project that the present invention is provided In, sodium alginate is by NaIO4Aoxidize adjacent hydroxyl groups formation aldehyde radical, the amino in subsequent methacrylic acid -2- amino-ethyl esters with Carboxyl in aldehyde radical alginic acid passes through amidation process formation esterification aldehyde sodium alginate.Presence of the gelatin in carbodiimides Lower and ethylenediamine is condensed to form amination gelatin.It is first, modified when modified sodium alginate solution is mixed with modified gelatin solution The first layer network of schiff base reaction formation hydrogel occurs for amino in aldehyde radical and modified gelatin in sodium alginate.Then, change Property sodium alginate in methacrylic acid group in the presence of light trigger I2959 using 365nm it is ultraviolet trigger crosslinking, formed Second layer network of hydrogel.
The two-component of the present invention forms can be designed so that in practical operation of double cross-linked network hydrogels, two kinds of solution by Two syringes are expelled to mixing in same syringe needle and are allowed to occur schiff base reaction simultaneously, at room temperature it is spontaneous be cross-linked to form it is solidifying Glue.Required tissue site is expelled to, in-situ injection crosslinking is formed.
What the two-component of the present invention formed double cross-linked network hydrogels can be designed so that the hydrogel finally given has In stronger mechanical property, actual test, the hydrogel after swelling equilibrium has 2.5MPa modulus of compressibility value.
The design that the two-component of the present invention forms double cross-linked network hydrogels allows hydrogel scaffold to be handed over by adjusting Connection density reaches controllable degradation property.
Beneficial effect
(1) sodium alginate selected in the present invention and gelatin are natural biologic materials, nontoxic, tasteless, have well Biocompatibility, cheap, safe and reliable, in practical operation, two kinds of solution are expelled to same pin simultaneously by two syringes Mixed in head, dual network structure is formed by illumination, it is simple to operate；
(2) double-network hydrogel for preparing of the present invention is degradable, good mechanical property, be expected to be applied in organizational project can Inject hydrogel scaffold.
Brief description of the drawings
Fig. 1 is the preparation principle figure for being esterified aldehyde sodium alginate；Wherein n ≈ 7272；
Fig. 2 is the preparation principle figure of amination gelatin；
Fig. 3 is the preparation principle figure (a) and schematic diagram (b) of double cross-linked hydrogels；
Fig. 4 is the degraded schematic diagram of double cross-linked hydrogels；
Fig. 5 is the cell proliferative conditions that fibroblast joins hydrogel surface in double cross；
Fig. 6 is the schematic diagram for testing double-network hydrogel to the adhesion strength of tunica fibrosa；
Wherein, the ASA in accompanying drawing represents aldehyde sodium alginate, and AMSA represents to be esterified aldehyde sodium alginate, and AG represents amino Change gelatin.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.In addition, it is to be understood that after the content of the invention lectured has been read, people in the art Member can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited Scope.
Embodiment 1
It is accurate weigh 3.96g sodium alginates and be dissolved in 400ml deionized waters form uniform solution.By 4.28g periodic acid Sodium lucifuge is dissolved in appropriate deionized water, then sodium periodate solution lucifuge is added dropwise in homogeneous sodium alginate soln, And react 4h in lucifuge under normal temperature.Product is fitted into dialysis 3 days in bag filter (molecular cut off is 14000), time water is changed per 4h. Product is poured into plate the pre-freeze 6h in -80 DEG C of refrigerators, freeze dryer is subsequently placed into, freeze-drying obtains aldehyde radical alginic acid Sodium.
Embodiment 2
It is accurate weigh 1.2g aldehyde radical sodium alginates and be dissolved in 120mlMes buffer solutions form homogeneous solution.Will 1.1736g carbodiimides and 0.23064g HOSu NHSs are dissolved in appropriate Mes buffer solutions, are activated under the conditions of 37 DEG C 30~45min, then weigh the Mes solution lucifuges of 0.4995 methacrylic acid -2- amino-ethyl esters and be added dropwise, and under normal temperature Lucifuge reaction is stayed overnight.Product is fitted into lucifuge in bag filter (molecular cut off is 3500) to dialyse 3 days, time water is changed per 4h.Will production Thing pours into plate the pre-freeze 6h in -80 DEG C of refrigerators, is subsequently placed into freeze dryer, and freeze-drying obtains being esterified aldehyde radical alginic acid Sodium.
Embodiment 3
Accurately weigh 5g Bos taurus domesticus Gmelins to be dissolved in the 100ml aqueous solution, add 16ml ethylenediamines, adjust PH to 5.0, add 0.66g water-soluble carbodiimides EDC, 37 DEG C of reactions are stayed overnight.It is cooled to after room temperature, product is loaded into bag filter (retention molecule Measure 3500) to dialyse 3 days, time water is changed per 4h.Product is poured into plate and the pre-freeze 6h in -80 DEG C of refrigerators, is subsequently placed into lyophilized Machine, obtains amination gelatin.
Embodiment 4
Aldehyde sodium alginate (embodiment 2) will be esterified and be made into the solution that concentration is 30%.Precise amination gelatin is (real Apply example 3), concentration is made into deionized water for 20% solution.The aminated gelatin solutions of 1ml are taken with 2ml needle tubing, 2ml needle tubings are used Take 1ml to be esterified aldehyde sodium alginate solution, then add I2959 photo-initiated crosslinking agent, make its final mass body in system Product percentage concentration is 0.1%.Connected through a Y types, by aminated gelatin solution and esterification aldehyde sodium alginate solution simultaneously by one Individual needle injection forms column list network aqueous gel into 48 orifice plates.After 10min, in 365nm wavelength, 5Mw/cm2The purple of power 10~15min is irradiated under outer lamp, double cross-linked network hydrogels are produced.
Embodiment 5
The method according to embodiment 4, prepares cylindrical double cross connection water-setting blob, at room temperature in phosphate buffer (PH =7.4) in immersion 24h after, experiment is compressed to hydrogel using universal testing machine (Dejie DXLL-20000), is obtained The modulus of compressibility for going out hydrogel is 2.5MPa.
Embodiment 6
The method according to embodiment 4, prepares cylindrical double cross connection water-setting blob, is immersed at room temperature in deionization, fixed Phase takes out freeze-drying, weighs, calculates degradation curve.As shown in figure 4, double cross-linked hydrogels are decomposed in most junior one week 40% quality, the quality for still keeping about 50% on the 30th day.
Embodiment 7
Aldehyde sodium alginate (embodiment 2) will be esterified and amination gelatin (embodiment 3) is irradiated under 284nm uviol lamps and gone out Bacterium, according to being that method shown in embodiment 4 prepares the double cross-linked hydrogels of cylinder.Fibroblast is planted in hydrogel surface, Cell density is set as 10,000/ml.Cultivate after the scheduled time, by MTT methods of testing come test cell activity.It is planted in hole The conduct control of plate (TCP).As shown in figure 5, the natural material in hydrogel can promote the growth of cell, it was demonstrated that double cross connection Hydrogel has good biocompatibility.
Embodiment 8
Aldehyde radical alginic acid (embodiment 2) will be esterified and be made into the solution that concentration is 30%.Precise amination gelatin (is implemented Example 3), concentration is made into deionized water for 20% solution.The aminated gelatin solutions of 1ml are taken with 2ml needle tubing, are taken with 2ml needle tubings 1ml is esterified aldehyde sodium alginate solution, then adds the final mass volume hundred that I2959 photo-initiated crosslinking agent makes it in system It is 0.1% to divide concentration.Connected through a Y types, by aminated gelatin solution and esterification aldehyde sodium alginate solution simultaneously by a pin Head is expelled to the cm section of 1 cm x 1 in the PCL tunica fibrosas of 3 centimetres of 1 centimeter length of two panels, stands 10min formation column list nets Network hydrogel, then irradiates 10~15min under 365nm wavelength, the uviol lamp of 5Mw/cm2 power, to ensure that the double cross is networked Network hydrogel bonds two panels tunica fibrosa and completed.Stretched test (such as Fig. 6) understands that the double-network hydrogel glues to tunica fibrosa Knotting strength can reach more than 23.4Kpa.Result above, which shows that the double-network hydrogel is potential, to be used to bond the film class group such as meninx Knit.

Claims (10)

1. a kind of sodium alginate/glutin injectable double-network hydrogel, it is characterised in that：The hydrogel raw material includes：Esterification Aldehyde sodium alginate and amination gelatin, wherein the aldehyde sodium alginate and the mass ratio of amination gelatin that are esterified be 0.75~ 1.5:1。
2. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel as claimed in claim 1, including：Will The esterification aldehyde sodium alginate aqueous solution is mixed with the aqueous solution of amination gelatin, is crosslinked at 37 DEG C after 5-15min, then carry out purple External exposure is crosslinked, and produces sodium alginate/glutin injectable double-network hydrogel.
3. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel according to claim 2, its feature It is：The quality concentration of volume percent of the esterification aldehyde sodium alginate aqueous solution is 20%-30%；Amination gelatin is water-soluble The quality concentration expressed in percentage by volume of liquid is 20%.
4. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel according to claim 2, its feature It is：It is described esterification aldehyde sodium alginate preparation be specially：(1) under the conditions of room temperature lucifuge, the sodium metaperiodate aqueous solution is added Into the aqueous solution of sodium alginate, 4~6h is reacted, is dialysed, freeze-drying obtains aldehyde radical sodium alginate；Wherein sodium metaperiodate Molar ratio with sodium alginate is 0.88~1：1；(2) in the ethyl sulfonic acid Mes buffer solutions of aldehyde radical sodium alginate, carbon is added Change diimine and HOSu NHS, lucifuge activation 30-45min, is subsequently added methacrylic acid -2- amino-ethyls at room temperature React and stay overnight under the conditions of ester hydrochloride, room temperature lucifuge, dialyse, freeze-drying obtains being esterified aldehyde sodium alginate；Wherein aldehyde radical The mol ratio of carboxyl, carbodiimides, HOSu NHS and methacrylic acid -2- amino-ethyl esters on sodium alginate is 3：3：1：1.5.
5. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel according to claim 4, its feature It is：Sodium alginate is middle viscosity 580mpa.s sodium alginates in the step (1), and weight average molecular weight is about 1,440,000, G blocks Ratio is 40%.
6. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel according to claim 2, its feature It is：The preparation method of the amination gelatin includes：Ethylenediamine is added in aqueous gelatin solution, pH to 5.0 is adjusted, added Water-soluble carbodiimide EDC, 37 DEG C of 4~6h of reaction, dialyse, freeze-drying obtains amination gelatin；Wherein gelatin and ethylenediamine Mol ratio be 1：1；Gelatin is 1 with water-soluble carbodiimide mol ratio：2.
7. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel according to claim 6, its feature It is：The gelatin is Bos taurus domesticus Gmelin, and jelly force intensity is 150~180g, and viscosity 3.5~4.3, weight average molecular weight is about 3.7 ten thousand.
8. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel according to claim 2, its feature It is：The ultraviolet generator used in ultraviolet irradiation crosslinking is wavelength 365nm, power 5mw/cm2Uviol lamp, ultraviolet irradiation hand over Join 10~15min.
9. a kind of preparation method of sodium alginate/glutin injectable double-network hydrogel according to claim 2, its feature It is：Light trigger, the final mass concentration expressed in percentage by volume of the light trigger of use in system are used in ultraviolet irradiation crosslinking For 0.1%.
10. a kind of application of sodium alginate/glutin injectable double-network hydrogel as claimed in claim 1, it is characterised in that： Sodium alginate/glutin injectable double-network hydrogel is applied to the photo-crosslinking injection aquagel support in organizational project.
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