CN107753421A - A kind of antibiont adhesion polyelectrolyte hydrogel and preparation method and application - Google Patents
A kind of antibiont adhesion polyelectrolyte hydrogel and preparation method and application Download PDFInfo
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- CN107753421A CN107753421A CN201711086684.1A CN201711086684A CN107753421A CN 107753421 A CN107753421 A CN 107753421A CN 201711086684 A CN201711086684 A CN 201711086684A CN 107753421 A CN107753421 A CN 107753421A
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- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- WZAPMUSQALINQD-UHFFFAOYSA-M potassium;ethenyl sulfate Chemical compound [K+].[O-]S(=O)(=O)OC=C WZAPMUSQALINQD-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 229910001631 strontium chloride Inorganic materials 0.000 description 1
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0052—Mixtures of macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
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Abstract
本发明涉及一种抗生物粘附聚电解质水凝胶及制备方法及应用。将一种或几种带有相反电荷的聚电解质高分子溶液，以电荷比为1:1均匀混合，带有相反电荷的聚电解质高分子通过物理交联或化学交联方法或两种组合的方法形成水凝胶，此时正负电达到平衡，形成的水凝胶呈电中性。本发明的提供的制备聚电解质水凝胶的方法简单，容易操作，所制备的水凝胶具有良好的抗蛋白吸附性质，含水量高，在体内不会引起炎症反应，有利于移植物与机体之间的传质。因此，能够广泛应用于生物医疗领域，如胰岛细胞包裹治疗糖尿病，用作药物释放载体，伤口敷料，组织修复支架材料等。
The invention relates to an anti-bioadhesion polyelectrolyte hydrogel, a preparation method and application thereof. One or several polyelectrolyte polymer solutions with opposite charges are uniformly mixed at a charge ratio of 1:1, and the polyelectrolyte polymers with opposite charges are physically cross-linked or chemically cross-linked or a combination of the two The method forms a hydrogel, and at this time, the positive and negative charges are balanced, and the formed hydrogel is electrically neutral. The method for preparing the polyelectrolyte hydrogel provided by the present invention is simple and easy to operate. The prepared hydrogel has good anti-protein adsorption properties, high water content, and does not cause inflammatory reactions in the body, which is beneficial to the graft and the body. Mass transfer between. Therefore, it can be widely used in the field of biomedicine, such as encapsulation of pancreatic islet cells to treat diabetes, as a drug release carrier, wound dressing, tissue repair scaffold material, etc.
Description
Technical field
The invention belongs to biomedical materials field, and in particular to one kind is by the polyelectrolyte macromolecule with opposite charges
Composition, and the biocompatible hydrogel material with antibiont sticking property.The invention further relates to the preparation of the hydrogel
Method and its application in biologic medical field.
Background technology
With the fast development of life science and material science, bio-medical material has turned into the mankind to be had with what disease was resisted
One of effect instrument.As implantable medical device (embedded type sensor) can quickly and easily monitor various health datas in time,
Accuracy is high；Tissue engineering bracket material can be combined with histocyte, replaced tissue or organ that patient is damaged, controlled for the mankind
Treat tissue damage and provide new selection；Drug release carrier can target efficiently release medicament in affected area, be human treatment
Cancer provides a kind of effective measures；Microencapsulated cell implantation technique (such as islet cells encapsulating) can effectively play immune
Buffer action, new way is opened for cell transplant techniques.However, these exogenous materials with body when contacting, it is especially long
When time implants, often cause body to produce strong immunological rejection, cause material surface fine and close by one layer
Collagenous fibres capsule is wrapped up, and is isolated with destination organization, ultimately results in implantation material failure, while brings pain and secondary to patient
The risk of operation.
Research finds that material rear this caused series of biologic reaction in transplant is due to that bioadhesion is made
Into.Bioadhesion refers to large biological molecule (protein), and cell and microorganism etc. are sent out in biomaterial surface and various interfaces
Raw unnecessary absorption.When these exogenous materials implant, it happens is that a large amount of protein in the non-of material surface first
Specific adsorption, so as to cause a series of subsequent biologicallies, such as immunological rejection, foreign body reaction and fiber scrotiform
Into.Therefore, the nonspecific proteins absorption of bio-medical material, that is, its antibiont adhesion energy improved are farthest reduced
Power, it is the important channel for improving medical material biocompatibility, while is also great demand and the challenge of field of medical materials.
At present, amphion hydrogel material (such as Phosphorylcholine, carboxybetaine and sulfonic group glycine betaine etc.) is considered as
It is one of most promising stain resistant material.Zwitterionic materials can effectively suppress large biological molecule (protein), and cell glues
It is attached, and there is good histocompatbility.Its Antifouling mechanism mainly has at following 2 points：(1) amphion is real by electrostatic interaction
Existing high degree of hydration, so as to which the hydrated sheath formed in molecular surface greatly hinders large biological molecule (such as protein) and thin
Bacterium, cell stick；(2) due to amphion molecule on same monomeric unit simultaneous with a positive charge and a negative electricity
Lotus, so it is in electroneutral that its is apparent, and large biological molecule, bacterium and cell etc. be often with positive or negative electricity, therefore they it
Between electrostatic interaction it is extremely weak, cause these charge specieses can not stablize be attached to hydrogel surface.In summary, by both sexes from
The inspiration of the unique texture and excellent properties of son, further develops simpler easy method, and preparing has antibiont adhesion
The polyelectrolyte hydrogel of ability simultaneously is expected to that bio-medical field can be widely used in.
The content of the invention
The purpose of the present invention aims to provide a kind of preparation method of efficient easily antibiont adhesion polyelectrolyte hydrogel
And application.The antibiont adhesion polyelectrolyte hydrogel of the present invention, has anti-albumen, cell, bacterium, blood sticking property, and
Vivo immunization rejection can effectively be weakened after in transplant, suppress fibrous capsule and formed, available for cell micro-encapsulation technology,
Either as wound dressing materials or as organizational project repair materials；In addition, this method method is simple to operate, condition temperature
With, it is not necessary to complicated chemical synthesis process, it is a kind of method for preferably preparing antibiont adhesion hydrogel.
The first object of the present invention be to provide it is a kind of prepare the polyelectrolyte hydrogel with antibiont sticking property, have
Anti- albumen, cell, bacterium, blood adhesion function, and be transplanted in vivo can anti-immunity repulsive interaction and suppress fiber scrotiform
Into.
The second object of the present invention is to provide the preparation method of above-mentioned antibiont adhesion polyelectrolyte hydrogel.
The third object of the present invention is to provide above-mentioned antibiont adhesion polyelectrolyte hydrogel answering in terms of bio-medical
With.
To achieve these goals, the present invention prepared by antibiont adhesion polyelectrolyte hydrogel method be by with
Lower technical scheme is realized：
A kind of antibiont adhesion polyelectrolyte hydrogel of the present invention, be one be in electroneutral hydrogel, surface
Electric charge is 0.By simulating amphion electroneutral property, by with one or more of opposite charges polyelectrolyte macromolecule
I.e. polyanion and polycation are 1 by charge ratio:1 mixing, makes positive and negative charge reach poised state, polyelectrolyte macromolecule leads to
The method for crossing the combination of one or both of Physical cross linking methods or Chemical Crosslinking Methods forms hydrogel, the hydrogel formed
In electroneutral, there is good antibiont adhesive capacity.
Physical cross linking methods prepare a kind of polyelectrolyte hydrogel of antibiont sticking property, and its step is as follows：
(1) arbitrary polyanion or said polycation solution are prepared；
(2) colloid titration polyanion or said polycation solution charge number are used；
(3) polyanion or said polycation solution prepared in step (1) are poured into mould；
(4) polycation or polyanion solution with polyelectrolyte opposite charge described in step (1) are prepared；
(5) charge number of polycation or polyanion solution described in colloid titration step (4)；
(6) will carry poly- sun described in step (4) with polyelectrolyte solution identical charges number described in step (1) from
The solution of son or polyanion, is added dropwise in the mould described in step (3) and stirs；Polyelectrolyte with opposite charges
Macromolecule is cross-linked to form polyelectrolyte hydrogel by electrostatic self-assembled or addition bivalent cation auxiliary, and now positive and negative charge reaches
To balance, system is in electroneutral, and determines zeta current potentials, as shown in Figure 1.
Chemical Crosslinking Methods prepare a kind of polyelectrolyte hydrogel of antibiont sticking property, and its step is as follows：
(1) arbitrary polyanion or said polycation solution are prepared；
(2) colloid titration polyanion or said polycation solution charge number are used；
(3) polyanion or said polycation solution prepared in step (1) are poured into mould；
(4) polycation or polyanion solution with polyelectrolyte opposite charge described in step (1) are prepared；
(5) charge number of polycation or polyanion solution described in colloid titration step (4)；
(6) corresponding anionic group or cation group activator are added in the mould described in step (3), stirring is equal
It is even, then it is added dropwise and the polycation described in the step (4) of polyelectrolyte solution identical charges number described in step (1)
Or the solution of polyanion, polyelectrolyte hydrogel is obtained by chemical crosslink reaction.Polyanion and polycation used
The electrically charged density of institute is 1:1, the hydrogel of formation is in electroneutral, and determines zeta current potentials.
Chemically and physically crosslinking mixing method prepares antibiont adhesion polyelectrolyte hydrogel, and its step is as follows：
(1) arbitrary polyanion or said polycation solution are prepared；
(2) colloid titration polyanion or said polycation solution charge number are used；
(3) polyanion or said polycation solution prepared in step (1) are poured into mould；
(4) polycation or polyanion solution with polyelectrolyte opposite charge described in step (1) are prepared；
(5) charge number of polycation or polyanion solution described in colloid titration step (4)；
(6) will carry poly- sun described in step (4) with polyelectrolyte solution identical charges number described in step (1) from
The solution of son or polyanion, is added dropwise in the mould described in step (3) and stirs, the polyelectrolyte with different electric charges
Macromolecule forms hydrogel under electrostatic force；
(7) anion active agent solution and condensation agent solution are then added, makes the electroneutral polyelectrolyte hydrogel to be formed
Further crosslinking.
Polyelectrolyte macromolecule used can arbitrarily carry a kind of water soluble polymer of ionizing group in the present invention.
The heretofore described polymer containing polyanion is various alginates, hyaluronate, CMS,
One or two or more kinds of compositions in carboxymethyl cellulose, polyacrylic acid and above-mentioned polyanionic polymer, molecular weight exist
1kDa~2500kDa.
The heretofore described polymer containing polycation is branched polyethylenimine, straight linear polyethylene imines, shell gather
One or both of sugar, chitosan oligosaccharide, Quaterisation chitosan, α-polylysine, poly arginine and above-mentioned polycationic polymer
Composition above, molecular weight is in 1kDa~1000kDa.
Physical cross linking methods of the present invention be electrostatic self-assembled, bivalent cation for example calcium ion, barium ions, strontium from
Son, nickel ion or copper ion crosslinking.
Chemical Crosslinking Methods of the present invention are amino and carboxyl condensation reaction is condensing agent method, first add activator by anion
Activated carboxylic, condensing agent is added, amino and carboxyl are condensed；Wherein the combination of activator and condensing agent includes 1- (3- diformazans
Aminopropyl) -3- ethyl-carbodiimide hydrochlorides/n-hydroxysuccinimide (EDC/NHS), 1- (3- dimethylamino-propyls) -
3- ethyl-carbodiimide hydrochlorides/I-hydroxybenzotriazole (EDC/HOBt).
Polyelectrolyte hydrogel of the present invention is that the electrically charged amount of polyanion institute is with the electrically charged amount of polycation
1:1, surface charge 0, zeta current potentials are between -5~5mV.
The application of the present invention is as follows：
Heretofore described preparation method, when using sodium alginate as polyanionic polymer, electrostatic liquid can be used
Drop method prepares the hydrogel microsphere with antibiont sticking property, is by charge ratio with said polycation solution by sodium alginate soln
1：1 it is well mixed after add microsyringe, be injected to by 14KV HV generators equipped with bivalent cation solution
In collector, solidify 30min, collect obtained hydrogel microsphere.
Antibiont of the present invention adhesion polyelectrolyte hydrogel can be used for microencapsulation, by one kind of living cells or
Two kinds are embedded in above-mentioned hydrogel or hydrogel microsphere, and hydrogel can maintain cytoactive, and realize that anti-immunity is arranged in vivo
The effect of reprimand.Described living cells is behaved or the in vitro living cells of animal origin, including on islet cells, thyroid cell, kidney
Gland medullary epithelium, other gland cells, stem cell, nerve cell, muscle cell, cortex cell, haemocyte, lymphocyte and embryo
At least one of tire class cell.
Wherein, antibiont adhesion polyelectrolyte hydrogel of the present invention is in encapsulating islet cells treatment diabetic mice
During model, it can effectively suppress the immunization inflammatory reaction of blood mediation, significantly alleviate diabetic symptom, maintain mouse blood sugar
Normal level.
The heretofore described polyelectrolyte hydrogel with antibiont sticking property can be used as wound dressing, because of institute
Stating hydrogel has good hydrophily, can be used alone as dressing or wherein add antiseptic, the antiseptic includes nanometer
The medicine of silver, chitosan or quaternary ammonium salt.
The heretofore described polyelectrolyte hydrogel with antibiont sticking property can encapsulate growth factor, activity
Material etc. is used for tissue repair, reaches the effect of sustained release, while can also overcome vivo immunization rejection.Described growth factor
Including active material and growth factor, wherein bioactive substance includes one or both of enzyme, protein, polypeptide, hormone.
Growth factor includes VEGF (VEGF), fibroblast growth factor (FGF), transforming growth factor β (TGF
β)。
The positive effect of the present invention is：
1) the inventive method process condition is gentle, simple to operate, no coupling product, non-toxic, and need not add catalyst,
Be advantageous to maintain cytoactive.
2) hydrogel of the present invention has excellent anti-protein adsorption, Anti cell adhesion, anti-bacterial attachment and anti-blood
Liquid sticking property.
3) above-mentioned anti-soil hydrogel can effectively weaken immunological rejection implanting, and suppress fibrous capsule and formed,
With superior function of immune isolation, immune isolated material can be widely used as, immunocyte, which can not enter inside hydrogel, to kill
Dead cell, the permeability of hydrogel in itself is maintained, is advantageous to mass transfer.
Brief description of the drawings
Fig. 1 is polyelectrolyte hydrogel preparation principle schematic diagram in the present invention.
Fig. 2 is polyelectrolyte hydrogel in the present invention to FITC-BSA protein adsorption quantities.
Fig. 3 is to carry the anti-protein adsorption schematic diagram of different electric charge polyelectrolyte hydrogels in the present invention
Fig. 4 is that sodium alginate-polyethyleneimine hydrogel in the present invention prepared by embodiment 1 wraps up for islet cells
Treat type i diabetes design sketch.
Embodiment
By the following examples, technical scheme is described in further detail, but the present invention is not
It is confined to the following examples.
A kind of antibiont adhesion polyelectrolyte hydrogel in the present invention, its colloid titration polyelectrolyte institute are powered
Lotus density is tested as follows：
1mmol/L potassium polyvinyl sulfates (PVSK) solution is as standard anionic polymer solution, and poly- the two of 1mmol/L
Propylene alkyl dimethyl ammonium chloride (PDMDAAC) solution uses grain as cationic polymer, 0.1% toluidine blue as indicator
Charge of the electron analyzer determines the charge density of respective sample.Polyelectrolyte solution to be measured is added to the analysis room of instrument, added dropwise
Enter the standard polyelectrolyte solution with testing sample opposite charges, when solution is changed into brilliant violet color (color is not returned in 1min) from blueness,
When streaming potential is classified as rapidly 0, titration end-point is reached, records the amount V of the standard polyelectrolyte solution of consumptionConsumption。
Charge density (mmol/g)=VConsumption×CStandard/mSample quality。
Embodiment 1：The preparation of sodium alginate-polyethyleneimine hydrogel
0.5g sodium alginate powders (molecular weight 300kDa) are dissolved in 50mL ultra-pure waters, are stirred overnight, obtain quality
The sodium alginate soln that fraction is 1% is polyanionic polymer solution, and measure charge density is 0.68mmol/g.By 1g side chains
Polyethyleneimine (molecular weight 70kDa) is dissolved in 100mL ultra-pure waters, prepares the polyethylenimine solution that mass fraction is 1%
As polycationic polymer solution, measure charge density is 14.96mmol/g.
Take 1mL sodium alginate solns to add in small beaker, marine alga then is added dropwise in 0.045mL polyethylenimine solutions
Mixing is sufficiently stirred in acid sodium solution, now the charge density of polyanion sodium alginate and polycation polyethyleneimine is 1:
1,150 μ L are slowly added to, the crosslinking of 10% calcium chloride solution, sodium alginate-polyethyleneimine hydrogel is obtained, determines zeta current potentials
For 0.4mV.
Embodiment 2：The preparation of sodium alginate-straight linear polyethylene imines polyelectrolyte hydrogel
1g sodium alginate powders (molecular weight 300kDa) are dissolved in 100mL ultra-pure waters, are stirred overnight, obtain quality point
Number is polyanionic polymer solution for 1% sodium alginate soln, and measure charge density is 0.68mmol/g.1g straight chains are gathered
Aziridine (molecular weight 1.8kDa) is dissolved in 100mL ultra-pure waters, is prepared the polyethylenimine solution that mass fraction is 1% and is made
For polycationic polymer solution, measure charge density is 2.27mmol/g.
Take 1mL sodium alginate solns to add in small beaker, it is molten that sodium alginate is added dropwise in 0.3mL polyethylenimine solutions
Fully mixed in liquid, now the charge density of polyanion sodium alginate and polycation polyethyleneimine is 1:1, it is slowly added to
150 μ L, the crosslinking of 10% calcium chloride solution, sodium alginate-polyethyleneimine hydrogel is obtained, measure zeta current potentials are -2.8mV.
Embodiment 3：The preparation of hyaluronic acid-Quaterisation chitosan polyelectrolyte hydrogel
2g hyaluronic acid powders (molecular weight 250kDa) are dissolved in 100mL ultra-pure waters, are stirred overnight, obtain quality point
The hyaluronic acid solution that number is 2% is as anionic polymer solution, charge density 0.13mmol/g.By the quaternary ammoniated shells of 0.1g
Glycan (grafting degree 40%~50%, molecular weight 100kDa) is dissolved in 100mL ultra-pure waters, prepares mass fraction as 0.1%
Quaterisation chitosan solution as polycationic polymer solution, measure charge density is 10.6mmol/g.
Take 1mL hyaluronic acid solutions to add in small beaker, hyalomitome is added dropwise in 0.025mL Quaterisation chitosan solution
Fully mixed in acid solution, now the charge density of polyanion hyaluronic acid and polycation Quaterisation chitosan is 1:1, obtain
To hyaluronic acid-Quaterisation chitosan hydrogel, zeta current potentials are -5mV.
Embodiment 4：The preparation of sodium alginate-chitosan hydrogel
2g sodium alginates (molecular weight 200kDa) are dissolved in 100mL ultra-pure waters, are stirred overnight, obtaining mass fraction is
For 2% sodium alginate soln as polyanion solution, measure charge density is 0.42mmol/g.By 0.1g chitosans (de- second
Acyl degree is dissolved in 100mL 0.1% acetic acid for 90%) (molecular weight 1000kDa), is prepared the shell that mass fraction is 0.1% and is gathered
It is 19.5mmol/g that sugar juice is crosslinked measure charge density as said polycation solution.
Take 1mL sodium alginate solns to add in small beaker, 0.43mL chitosan solutions are slowly added to sodium alginate dropwise
Fully mixed in solution, now the charge density of polyanion sodium alginate and polycation chitosan is 1:1, it is slowly added to
150 μ L, 10% strontium chloride solution obtain sodium alginate-chitosan hydrogel, and zeta current potentials are -3.6mV.
Embodiment 5：The preparation of carboxymethyl cellulose-poly arginine hydrogel
2g carboxymethyl celluloses (molecular weight 70kDa) are dissolved in 100mL ultra-pure waters, are stirred overnight, obtain quality
For the cmc soln that fraction is 2% as polyanionic polymer solution, measure charge density is 0.98mmol/g.Will
0.5g poly arginines (molecular weight 1kDa) are dissolved in 100mL ultra-pure waters, and it is molten to prepare the poly arginine that mass fraction is 0.5%
For liquid as said polycation solution, measure charge density is 8.16mmol/g.
Take 1mL cmc solns to add in small beaker, carboxymethyl is added dropwise in 0.48mL poly arginine solution
Mixing is sufficiently stirred in cellulose solution, obtains carboxymethyl cellulose-poly arginine hydrogel.Now polyanion carboxymethyl is fine
Dimension element and polycation poly arginine charge density are 1:1, the zeta current potentials of hydrogel are 5mV.
Embodiment 6：The preparation of polyacrylic acid-α-polylysine hydrogel
It is 0.1% 0.1g polyacrylic acid (molecular weight 2500kDa) to be dissolved in mass fraction is obtained in 100mL ultra-pure waters
Polyacrylic acid solution is as polyanionic polymer solution, measure charge density 21.3mmol/g.1.5g α-polylysine (is divided
Son amount 4kDa) be dissolved in 100mL ultra-pure waters, prepare mass fraction be 1.5% α-polylysin solution as polycation
Solution, measure charge density are 1.17mmol/g.
1mL α-polylysin solution is taken in small beaker, polyacrylic acid solution 0.83mL is added dropwise and is sufficiently mixed uniformly,
Obtain polyacrylic acid-α-polylysine hydrogel.Now polyanion carboxymethyl cellulose and polycation poly arginine electric charge
Density is 1:1, resulting hydrogel zeta current potentials are -2mV.
Embodiment 7：The preparation of sodium alginate/CMS-chitosan oligosaccharide hydrogel
1g sodium alginate powders (molecular weight 300kDa) are dissolved in 100mL ultra-pure waters, are stirred overnight, obtain quality point
Number is 1% sodium alginate soln.0.7g CMS (molecular weight 60kDa) is dissolved in 100mL ultra-pure water, stirred
Mix the carboxymethyl starch soln for overnight, obtaining that mass fraction is 0.7%.Sodium alginate and CMS are all that polyanion is molten
Liquid, charge density are respectively 0.68mmol/g and 2.6mmol/g.1.5g chitosan oligosaccharides (molecular weight 3kDa) are added to 100mL again
In ultra-pure water, the polyhistidyl solution 1.5% is obtained as said polycation solution, it is 1.25mmol/g to measure charge density.
Take sodium alginate and each 0.5mL of CMS to be mixed into small beaker respectively, then 2mL chitosan oligosaccharides are added dropwise
Fully mixed in mixed liquor, be slow added into the barium chlorides of 150 μ L 10% and be further crosslinked, obtained sodium alginate/carboxymethyl and form sediment
Powder-chitosan oligosaccharide hydrogel, zeta current potentials are -1.3mV.
Embodiment 8：Chemical crosslinking condensing agent method prepares sodium alginate-straight linear polyethylene imines hydrogel
0.5g sodium alginate powders (molecular weight 300kDa) are dissolved in 50mL ultra-pure waters, are stirred overnight, obtain quality
The sodium alginate soln that fraction is 1% is polyanionic polymer solution, and measure charge density is 0.68mmol/g.By 1g straight chains
Polyethyleneimine (molecular weight 1.8kDa) is dissolved in 100mL ultra-pure waters, prepares the polyethylenimine solution that mass fraction is 1%
As polycationic polymer solution, measure charge density is 2.76mmol/g.
10mL sodium alginate solns are added in round-bottomed flask, magneton stirring, pH4.0~5.5 is adjusted, adds activator
Carboxylic acid group on 1.2mmol 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC) activation sodium alginate
Group, the n-hydroxysuccinimide (NHS) for then adding 1.0mmol are used as crosslinking agent, are eventually adding 5.5mL straight linear polyethylenes Asia
Amine.The amino on carboxyl and polycation polyethyleneimine on polyanion sodium alginate is cross-linked to form altogether by dehydrating condensation
Valency cross-linked hydrogel.The electrically charged density of polyanion used and polycation institute is 1:1, the hydrogel of formation is in electroneutral,
Zeta current potentials are -0.3mV.
Embodiment 9：The preparation of mixing method hyaluronic acid-chitosan oligosaccharide hydrogel
2g hyaluronic acid powders (molecular weight 250kDa) are dissolved in 100mL ultra-pure waters, are stirred overnight, obtain quality point
The hyaluronic acid solution that number is 2% is as anionic polymer solution, charge density 0.13mmol/g.Again by 1.5g chitosan oligosaccharides
(molecular weight 3kDa) is added in 100mL ultra-pure waters, is obtained the polyhistidyl solution 1.5% as said polycation solution, is surveyed
It is 1.25mmol/g to obtain charge density.
10mL hyaluronic acid solutions are added in small beaker, 1.4mL chitosan oligosaccharide solution is slowly added dropwise and is sufficiently stirred mixing,
Form polyelectrolyte hydrogel.Add 1.0mmol 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC)
Hydroxy-acid group on activator solution activation hyaluronic acid, adjusts pH 4.0~5.5, adds 1.0mmol 1- hydroxy benzos
Triazole (HOBt) is used as crosslinking agent, passes through chemical crosslinking to the polyelectrolyte hydrogel of formation.
2nd, for polyelectrolyte hydrogel prepared in above-described embodiment, its antibiont sticking property is tested：
1st, anti-albumen adhesion test
Hydrogel is made to a diameter of 1cm circular sample with card punch, sample is immersed in fluorescein isothiocynate mark
Concentration is 0.1mg/mL in the bovine serum albumin solution of note, is placed in 37 degree of horizontal shakers and is incubated 2 hours, then uses physiological saline
Rinse 3 times, every time 5 minutes.The fluorescence indicator adsorption situation of hydrogel surface is observed under inverted microscope and calculates fluorescin suction
Attached amount (as shown in Figure 2).And the albumen adhered to by ELISA to hydrogel surface carries out quantitative test.When not having on hydrogel
When fluorescin adsorbs, and adsorbance is less than 1%, shows that hydrogel can effectively suppress albumen adhesion.
Test result：
The anti-albumen adhesion test result of prepared polyelectrolyte hydrogel is as shown in table 1 below in above-described embodiment：
Table 1：Polyelectrolyte hydrogel surface protein adherence amount
As shown in Table 1, compared with Sodium Alginate Hydrogel Films, the polyelectrolyte water-setting of the charge balance prepared by the present invention
Glue, because surface charge is in neutrality, the electrostatic interaction and hydrophobic interaction between surface and albumen can be effectively eliminated, therefore
With the significant effect for suppressing albumen adhesion, the principle of anti-albumen adhesion is as shown in Figure 3.
2nd, Anti cell adhesion is tested
Hydrogel sample is made to a diameter of 1cm circular sample with card punch, sterile sample is put into 48 orifice plates,
100uL concentration is 5 × 106Cell/mL fibroblast (NIH-3T3) hanging drop is added in hydrogel sample surface (orifice plate
Culture is as control), after 3 days, rinsed 3 times with PBS solution, remove nonadherent cell, observe water-setting under an optical microscope
Glue superficial cell adheres to situation, and it is N to record hydrogel surface adherent cell quantityHydrogel, blank control group NBlank, by as follows
Formula calculates cell adherence percentage.
Prepared polyelectrolyte hydrogel Anti cell adhesion test result is as shown in table 2 below in above-described embodiment：
Table 2：Polyelectrolyte hydrogel surface cell adherence (%)
As shown in Table 2, blank orifice plate as a control group, in contrast the present invention prepared by charge balance polyelectrolyte
Hydrogel can effectively prevent cell from being adhered in material surface, propagation, show stronger Anti cell adhesion property.
3rd, anti-bacterial attachment
Hydrogel is made to a diameter of 1cm circular sample with card punch, and above-mentioned hydrogel sample is immersed in large intestine
In bacillus bacterium solution (OD=1), 37 degrees Celsius of incubation 2h, with normal saline flushing, flushed gel sample is put into consolidating for LB
Overnight incubation on body culture medium, observe bacterium colony formational situation and count.
Prepared polyelectrolyte hydrogel anti-bacterial attachment test result is as shown in table 3 below in above-described embodiment：
Table 3：Polyelectrolyte hydrogel surface bacterial adhesion (C.F.U./cm2)
As shown in Table 3, compared with orifice plate control group, the polyelectrolyte hydrogel surface of the charge balance prepared by the present invention
Substantially there is no bacterial adhesion, show that it has good antibacterial sticking property.
4th, anti-blood adhesion and hemolysis rate
Hydrogel is made to a diameter of 5mm circular sample with card punch, hydrogel sample is incubated in new blood
30min, normal saline flushing observe blood coagulation situation afterwards twice.As a result hydrogel table prepared in above-mentioned 1-6 embodiments is shown
Face all without the phenomenon for finding blood coagulation, shows that prepared polyelectrolyte hydrogel can suppress haemocyte well in material
Surface adhesion
Haemolysis test is carried out to polyelectrolyte hydrogel, the blood compatibility of hydrogel is verified with this.By the water-setting of equivalent
Glue sample is respectively charged into centrifuge tube, adds 0.3mL mouse blood and 1.2mL physiological saline, after being well mixed, at 37 DEG C
It is incubated 30min.Positive control:The deionized water (not containing test sample) of fresh mouse blood and 1.2mL containing 0.3mL；It is negative
Control:0.9% NaCl solution (not containing test sample) of fresh mouse blood and 1.2mL containing 0.3mL.It is incubated and completes
Afterwards, 1000rpm centrifuges 10min, takes supernatant to determine absorbance under 541nm and calculates hemolysis rate.As bio-medical material, facing
In bed application, 5% is necessarily less than with the material hemolysis rate of contacting blood.
Wherein, AS is the absorbance of sample；AN is the absorbance of negative control；AP is the absorbance faced.
Prepared polyelectrolyte hydrogel hemolysis rate test result is as shown in table 4 below in above-described embodiment：
Table 4：Polyelectrolyte hydrogel hemolysis rate (%)
As shown in Table 4, the hemolysis rate of the polyelectrolyte hydrogel of the charge balance prepared by the present invention is respectively less than 5%, and
Close to 0%, showing the polyelectrolyte hydrogel of this charge balance has good blood compatibility, during with contacting blood,
Hemolytic reaction will not be caused.
5th, anti-immunity repels effect in polyelectrolyte water gel
Method as described in above-described embodiment 1-6 prepares poly- electrolysis hydrogel, hydrogel is made with card punch a diameter of
5mm circular sample, hydrogel sample heeling-in is subcutaneous to mouse, and sample and surrounding tissue, section are taken out in transplanting after three months
Macchiavello's staining analysis is whether its anti-immunity repels effect and have fibrous capsule to be formed afterwards, is further tested by calculating Collagen density
Whether card has fibrous capsule to be formed, and table 5 show Collagen density after different hydrogel heeling-ins.As a result show, after hydrogel transplanting
Obvious immunization inflammatory reaction is not caused, transplanting does not have substantial amounts of collagen deposition, Collagen density and normal structure after three months
There is no difference, surfacing has good histocompatbility, can avoid being identified by immunity of organism, and then suppresses fiber scrotiform
Into.
Table 5：Collagen density (%) after three months after the transplanting of polyelectrolyte water-setting
It can be seen from the above test that by balancing the polyelectrolyte water-setting prepared by the method for polyelectrolyte electric charge in the present invention
Glue can significantly suppress protein, cell, and bacterium adheres in hydrogel surface；And without tight after being transplanted in Mice Body
The inflammatory reaction of weight, and no fibrous capsule is formed.Showing the polyelectrolyte hydrogel of the charge balance prepared by the present invention has
The property of good antibiont adhesion and immunological rejection can be suppressed and fibrous capsule is formed, therefore in bio-medical field
With preferable application prospect.
3rd, application of the above-mentioned polyelectrolyte hydrogel in biomedical sector
Application examples 1：Polyelectrolyte hydrogel is used to embed islet cells for treating diabetes
According to the methods described of embodiment 1, sodium alginate-branched polyethylenimine water with antibiont sticking property is prepared
Gel.Mice Islet Cells are encapsulated in above-mentioned hydrogel, and are transplanted to diabetic mice abdominal cavity.As a result show, the present invention
Surface adheres to without immune protein after prepared hydrogel transplanting, compared with blank control group, the hydrogel prepared by the present invention
Can maintain for a long time (>100 days) activity of islet cells and insulin releasing efficiency, fast and stable regulation blood glucose, alleviate diabetes
Symptom, Sodium Alginate Hydrogel Films and pure islet cells are control group.Fig. 4 is the glycemic control result of first 100 days.
Application examples 2：The preparation of sodium alginate-polyethyleneimine hydrogel microsphere
The heretofore described polyelectrolyte hydrogel prepared using sodium alginate as polyanion electrolyte, equally can be with
Anti-soil hydrogel microsphere is prepared using electrostatic drop generation, in ratio described in embodiment 1, sodium alginate and polyethyleneimine mixed
Solution adds microsyringe, is ejected into by 14kV HV generators in the collector equipped with 10% ionic calcium soln,
Solidify 30min, obtain having sodium alginate-polyethyleneimine hydrogel microsphere.
Application examples 3：Polyelectrolyte hydrogel encapsulation mescenchymal stem cell is used for repair of cartilage
According to the methods described of embodiment 3, hyaluronic acid-Quaterisation chitosan water-setting with antibiont sticking property is prepared
Glue simultaneously encapsulates mesenchymal stem cells MSCs wherein.The hydrogel for having embedded stem cell is placed in rabbit femoral condyle articular cartilage damage
Traumatic part position.As a result surface, postoperative 4 weeks, it was observed that existing Subchondral drilling, defect cover one layer of white soft tissue at defect,
There is no obvious inflammatory reaction, can be worked well with surrounding normal cartilage good combination, surface reconditioning.
Application examples 4：Polyelectrolyte hydrogel is used as dressing
According to the methods described of embodiment 4, the sodium alginate-chitosan hydrogel with antibiont sticking property is prepared.Cause
The high-hydrophilic of hydrogel, and anti-protein adsorption and cell adherence, it is able to maintain that wound moist and will not causes allergic red
The problems such as swollen.Hydrogel sample is made to the disk of 1cm diameters, for cut wound mouse model Wound healing and bone regeneration.Since the 7th day,
Wound healing, at 14 days, the surface of a wound closes completely, is covered by newborn epithelial tissue.
Application examples 5：Polyelectrolyte hydrogel is growth factor-loaded
According to the methods described of embodiment 3, the hyaluronic acid-Quaterisation chitosan with antibiont sticking property can be obtained
Hydrogel.Existing document report TGF β -3 are advantageous to stimulate cell Osteoblast Differentiation, therefore are wrapped in preparation process in hydrogel
TGF β -3 are buried, and use it for rabbit cartilage damage model at one's knees.As a result show, postoperative 4 weeks, compared with blank control group, load
TGF β -3 hydrogel group, clear with surrounding normal cartilage interface, filler surfacing is smooth, anti-without obvious inflammation
Should, linked well with normal cartilage.
All methods that the present invention is disclosed and proposed, those skilled in the art can be appropriate to change by using for reference present disclosure
The link such as raw material and condition is realized, although the method for the present invention is described by preferred embodiment, correlation technique people
Member can substantially not depart from present invention, method described herein is being modified or reconfigured in spirit and scope, come
Realize final technology of preparing.In particular, all similar replacements and change come to those skilled in the art
Say it is it will be apparent that they are considered as being included in spiritual, scope and content of the invention.
Claims (10)
- A kind of 1. polyelectrolyte macromolecule hydrogel of antibiont adhesion；It is characterized in that polyelectrolyte of the balance with opposite charges Macromolecule, forms the polyelectrolyte hydrogel of electroneutral, and its surface charge is that 0, zeta current potentials are -5~5mV.
- 2. claim 1 antibiont adhesion polyelectrolyte hydrogel preparation method, it is characterized in that by with one kind or several The polyelectrolyte macromolecule of kind of opposite charges is that polyanion and polycation by charge ratio are 1:1 mixing, reaches positive and negative charge The side combined to poised state, polyelectrolyte macromolecule by one or both of Physical cross linking methods or Chemical Crosslinking Methods Method forms hydrogel, and the hydrogel formed is in electroneutral.
- 3. method as claimed in claim 2, it is characterized in that to prepare hydrogel step as follows for physical method：(1) polyanion or said polycation solution are prepared；(2) colloid titration polyanion or said polycation solution charge number are used；(3) polyanion or said polycation solution prepared in step (1) are poured into mould；(4) polycation or polyanion solution with polyelectrolyte opposite charge described in step (1) are prepared；(5) charge number of polycation or polyanion solution described in colloid titration step (4)；(6) will carry polycation described in step (4) with polyelectrolyte solution identical charges number described in step (1) or The solution of polyanion, under agitation, stirred in the mould in being added dropwise described in step (3)；With opposite The polyelectrolyte macromolecule of electric charge is cross-linked to form polyelectrolyte hydrogel by electrostatic self-assembled and addition bivalent cation auxiliary, Now positive and negative charge reaches balance, and system is in electroneutral, and determines zeta current potentials.
- 4. method as claimed in claim 2, it is characterized in that to prepare hydrogel step as follows for Chemical Crosslinking Methods(1) arbitrary polyanion or said polycation solution are prepared；(2) colloid titration polyanion or said polycation solution charge number are used；(3) polyanion or said polycation solution prepared in step (1) are poured into mould；(4) polycation or polyanion solution with polyelectrolyte opposite charge described in step (1) are prepared；(5) charge number of polycation or polyanion solution described in colloid titration step (4)；(6) corresponding anionic group or cation group activator are added in the mould described in step (3), stirred, with It is added dropwise afterwards and the polycation described in the step (4) of polyelectrolyte solution identical charges number described in step (1) or poly- The solution of anion, polyelectrolyte hydrogel is obtained by chemical crosslink reaction.Polyanion used and polycation institute band Charge density is 1:1, the hydrogel of formation is in electroneutral, and determines zeta current potentials.
- 5. a kind of method as described in claim 3 or 4, it is characterized in that polyelectrolyte macromolecule is arbitrarily to carry ionizing group Water soluble polymer.
- 6. the method as described in claim 3 or 4, it is characterized in that the polymer of polyanion is various alginates, hyalomitome One or two or more kinds in hydrochlorate, CMS, carboxymethyl cellulose, polyacrylic acid and above-mentioned polyanionic polymer Composition, molecular weight is in 1kDa~2500kDa.
- 7. the method as described in claim 3 or 4, it is characterized in that the polymer of polycation is branched polyethylenimine, straight chain Polyethyleneimine, chitosan, chitosan oligosaccharide, Quaterisation chitosan, α-polylysine, poly arginine and the polymerization of above-mentioned polycation Composition more than one or both of thing, molecular weight is in 1kDa~1000kDa.
- 8. antibiont adhesion polyelectrolyte hydrogel as claimed in claim 1 is applied to encapsulating islet cells can be effectively to glycosuria Sick mouse model is treated, and maintains blood glucose steady.
- 9. the antibiont adhesion polyelectrolyte hydrogel of claim 1 is applied to biologic medical field, including cell micro-encapsulation carries Body, wound dressing, growth factor-loaded tissue repair substitute timbering material and drug release carrier.
- 10. the antibiont described in claim 1 adheres to hydrogel as cell micro-encapsulation carrier, the cell encapsulated can be Human cell or zooblast include gland cell, body cell, stem cell, nerve cell, muscle cell, cortex cell, lymph At least one of cell, haemocyte and embryo's class cell.
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