CN106519634A - Injectable hydrogel forming by one-step physical-chemical method and preparation method thereof - Google Patents
Injectable hydrogel forming by one-step physical-chemical method and preparation method thereof Download PDFInfo
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- CN106519634A CN106519634A CN201611182092.5A CN201611182092A CN106519634A CN 106519634 A CN106519634 A CN 106519634A CN 201611182092 A CN201611182092 A CN 201611182092A CN 106519634 A CN106519634 A CN 106519634A
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- mal
- hydrogel
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- pamam
- polyethylene glycol
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- 238000000034 method Methods 0.000 title claims abstract description 49
- 239000000126 substance Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 39
- 150000002148 esters Chemical class 0.000 claims abstract description 32
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 29
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002994 raw material Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000002347 injection Methods 0.000 claims description 41
- 239000007924 injection Substances 0.000 claims description 41
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 34
- 150000001412 amines Chemical class 0.000 claims description 26
- 229920002647 polyamide Polymers 0.000 claims description 26
- 229920003023 plastic Polymers 0.000 claims description 25
- 239000004033 plastic Substances 0.000 claims description 25
- 239000004952 Polyamide Substances 0.000 claims description 23
- 239000000412 dendrimer Substances 0.000 claims description 6
- 229920000736 dendritic polymer Polymers 0.000 claims description 6
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 238000001879 gelation Methods 0.000 abstract description 30
- 238000010382 chemical cross-linking Methods 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 6
- 229920000962 poly(amidoamine) Polymers 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 17
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- 238000002156 mixing Methods 0.000 description 5
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- 108090000623 proteins and genes Proteins 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
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- RGZSQWQPBWRIAQ-HUUCEWRRSA-N (2r)-6-methyl-2-[(1s)-4-methylcyclohex-3-en-1-yl]hept-5-en-2-ol Chemical compound CC(C)=CCC[C@@](C)(O)[C@H]1CCC(C)=CC1 RGZSQWQPBWRIAQ-HUUCEWRRSA-N 0.000 description 2
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- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
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- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
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Abstract
The invention provides an injectable hydrogel formed by a one-step physical-chemical method, which comprises the following raw materials in percentage by mass: 5-35% of polyethylene glycol maleimide as active ester, 5% of polyamidoamine and the balance of water. The hydrogel combines physical and chemical crosslinking simultaneously, realizes one-step gelation, and has the advantages of easily obtained raw materials, simple preparation method and strong feasibility.
Description
Technical field
The invention belongs to medical biomaterial technical field, is related to a kind of injection aquagel, and in particular to one kind is based on
Injection aquagel of one one-step physical chemical method plastic and preparation method thereof.
Background technology
Injection aquagel be before pointed injection for working fluid, after syringe injects and subcutaneously or intramuscularly organizes, can be
The hydrogel of injection site gelatinizing-in-situ.Compared to traditional hydrogel, injection aquagel is applied to biomedicine field
With many excellent properties.When being such as applied to the encapsulating of medicine, gene or cell, various medicines can be loaded by simple physical mixed
Thing molecule, gene or cell, and the local administration and long-acting drug release of diseased region is realized, while medicine can also be kept to greatest extent
Thing, gene, the biological activity of cell；When being applied to organizational project, the liquid of injection can be erose full of entirely having
Defect, it is to avoid pre- plastotype timbering material is difficult to and repairs the defect of mate.Additionally, injection aquagel is without the need for outer
Section's operation implantation, it is to avoid operation wound and concurrent inflammation that embedded type timbering material brings.
According to the difference of gelation principle, injection aquagel is divided into two class of physical hydrogel and chemical hydrogel.At present
Generally injection aquagel is prepared using three kinds of methods：I () polymer stimulates such as pH changes, temperature change, light in response to various
Deng multi-level self assembly；(ii) vinyl monomer includes that the free radical in situ of PEG, PVA and polysaccharide of vinyl functionalization is handed over
Connection；(iii) polycondensation of macromole precursor such as Michael-type additive reaction, Diels-Alder reaction, schiff base reaction and Shi Taoding
Lattice coupled reaction.Wherein, the self assembly of polymer belongs to physical crosslinking, has the advantages that relatively mild cytotoxicity is little, and which coagulates
Gel process is typically reversible, and gained hydrogel has good self-healing performance.Even so, physical hydrogel is generally not
Such as chemical hydrogel is firm, and the structural stability of physical hydrogel also can not show a candle to chemical hydrogel.However, Chemical Crosslinking Methods
As the use of its relatively quick gelation process and cross-linking agent often has stronger cytotoxicity.
For solving the above problems, the double-network hydrogel based on the preparation of order multistep cross-linking method is by wide coverage, this
Method is to be physical crosslinking by being first physical crosslinking to be chemically crosslinked afterwards or be first chemically crosslinked afterwards.Its hydrogel for preparing has high
Mechanical strength (about tens MPas), the low-friction coefficient wearability suitable with natural cartilage, and excellent adjustable polyphony
Answer the characteristic of performance, heat stability and suitable cell culture.Although these features overcome traditional pure physical hydrogel or chemistry
The problems such as relatively poor mechanical performance of hydrogel and single-function, but the crosslinking of order multistep still faces many practical problems,
Such as there is complex steps, complicated and time-consuming gel process, and be difficult to the mol ratio of the every kind of component of precise control, cause final
The hydrogel poor plasticity of formation, 3D networks anisotropy and gel mechanical strength repeatability are limited.Therefore, in the urgent need to building
Vertical a kind of simpler and general method is realizing pure physical crosslinking and having complementary functions of being chemically crosslinked, and simplifies the friendship of order multistep
The loaded down with trivial details gelation process of connection.
The content of the invention
Based on above technical problem, the invention provides a kind of injectable water-setting based on an one-step physical chemical method plastic
Glue.The hydrogel realizes a step gelation in combination with physics and chemical crosslinking, and raw material is easy to get, and preparation method is simple, can
Row is strong.
In order to realize foregoing invention purpose, the present invention is adopted the following technical scheme that：
Based on the injection aquagel of an one-step physical chemical method plastic, it is made up of the raw material of following mass percent：Activity
Ester Polyethylene Glycol maleimide (NHS-PEG-MAL) 5-35% and Polyamide amine (PAMAM) 5%, balance of water.
Active ester Polyethylene Glycol maleimide of the present invention is 1～7 with the mass ratio of Polyamide amine:1, at this
Gelation rate in the range of mass ratio is highly suitable for in-situ injection, and gained gel pore is uniform, good mechanical property, plasticity
By force, cytotoxicity is little.
NHS-PEG-MAL and PAMAM can provide physics and chemical crosslinking site simultaneously, and be based on MAL and NH2Hydrogen bond make
With NHS and NH2Ester interchange, and π-π superpositions of MAL itself realize a step gelation.
Polyamide amine of the present invention is three generations's dendrimer.PAMAM algebraically less than three generations cannot plastic because
The PAMAM of low algebraically is rigidly poor, and dendritic structure stacking is loose, is unfavorable for plastic.
The molecular weight of active ester Polyethylene Glycol maleimide of the present invention is 5000Da.NHS-PEG-MAL molecular weight
Less than 5000Da cannot plastic because the PEG pliabilities of low-molecular-weight are poor, segment is shorter, it is impossible to which PAMAM molecule cross-links exist
Together.
The pH of injection aquagel of the present invention is 6～8.In acid condition (i.e. pH<6) under, NH2Easily protonate and form phase
Ammonium ion (the NH for answering3 +), cause MAL and NH2Between hydrogen bond reduce and even disappear, it is difficult to plastic；In alkalescence condition (i.e. pH>
8), under, the slow hydrolysis of MAL groups is likely to hinder the formation of hydrogen bond and hydrogel.
Present invention also offers the preparation method of the injection aquagel：At room temperature by active ester Polyethylene Glycol maleoyl
Imines and Polyamide amine are dissolved in the phosphate buffer that pH is 7.2-7.5 respectively, then are mixed in proportion, and obtain hydrogel.
The beneficial effects of the present invention is：
1st, injection aquagel of the invention can provide physics and chemical crosslinking site simultaneously, and be based on MAL and NH2's
Hydrogen bond action, based on NHS and NH2Ester interchange, and π-π superpositions of MAL itself realize a step gelation.
2nd, there is relatively rapid and highly toxic gelation process in traditional chemical crosslinking, and be physical crosslinking and there is machinery by force
The problems such as degree difference, for these shortcomings, present invention firstly provides the step cross-linking method that physics and chemical crosslinking are carried out simultaneously.Should
Method has many advantages, such as：1) with traditional chemical cross-linked phase ratio, due to introducing physical crosslinking site, its gel process is relatively warm
And safety；2) compared with conventional physical gel, due to introducing chemical crosslinking site, gained hydrogel has preferable mechanicalness
Can, and can be realized to gel time and machine by simply adjusting the concentration of two kinds of gel cells and the mol ratio of functional group
Tool performance it is highly controllable；3) with order multistep cross-linked phase ratio, with very simple and easily controllable gelatine step, gained
The 3D networks of gel have the homogeneity of height, and gel shape has excellent plasticity.
3rd, the present invention selects PAMAM and NHS-PEG-MAL for hydrogel raw material, and two kinds of raw materials can occur physics (hydrogen simultaneously
Key) and chemical (ester exchange) crosslinked action, and prepare simply, and realized commercialization.Therefore, which is selected and to this gellike side
The foundation of method, popularization and promote its application in organizational project and regenerative medicine that there is very important value.
Description of the drawings
It is 10%, 25% and the FT-IR spectrum of 40%w/v hydrogels that Fig. 1 is concentration of the present invention.
UV-vis light of the Fig. 2 for PAMAM, MAL-PEG-MAL and MAL-PEG-MAL/PAMAM aqueous solution of 0.1%w/v
Spectrum.
PH sensitivity schematic diagrams of the Fig. 3 for MAL-PEG-MAL/PAMAM hydrogels (25%w/v)
UV-vis spectrum of the Fig. 4 for the 4arm-PEG-MAL of 0.1%w/v.
Fig. 5 is MAL-PEG-MAL molecular weight and the dependent gelation behavior schematic diagram of PAMAM algebraically.
Fig. 6 is the TEM pictures of injection aquagel obtained in a step plastic method in the present invention, scale=500nm.
SEM photographs of the Fig. 7 for the NHS-PEG-MAL/PAMAM hydrogels of 10% (A1), 25% (A2) and 40%w/v (A3)
(illustration shows the SEM photograph of higher resolution under respective concentration), scale=10 μm；(B) NHS-PEG- of fresh preparation
The CLSM photos of MAL/PAMAM hydrogels (25%w/v), wherein PAMAM is by Cy5.5 fluorescent labelinies, scale=50 μm.
Rheological characteristics of the Fig. 8 for the NHS-PEG-MAL/PAMAM hydrogels of 10% (A1), 25% (A2) and 40%w/v (A3)
Energy；(B) NHS-PEG-MAL/PAMAM hydrogels of different shapes, scale=1cm.
Fig. 9 is HeLa cells (A1) and NIH 3T3 fibroblasts (A2) in 25%w/vNHS-PEG-MAL/PAMAM water
The CCK-8 detections of 12 hours, 24 hours and 48 hours are encapsulated in gel.(**：p<0.01, *：p<0.05, respectively with 12 hours
Corresponding concentration is compared).
Specific embodiment
The essentiality content of the present invention is described in further detail with reference to specific embodiment.
Embodiment 1
Based on the injection aquagel of an one-step physical chemical method plastic, it is made up of the raw material of following mass percent：Activity
Ester Polyethylene Glycol maleimide 5% and Polyamide amine 5%, balance of water.
Embodiment 2
Based on the injection aquagel of an one-step physical chemical method plastic, it is made up of the raw material of following mass percent：Activity
Ester Polyethylene Glycol maleimide 35% and Polyamide amine 5%, balance of water.
The molecular weight of the active ester Polyethylene Glycol maleimide is 5000Da.
Described Polyamide amine is three generations's dendrimer.
The pH of the injection aquagel is 8.
Embodiment 3
Based on the injection aquagel of an one-step physical chemical method plastic, it is made up of the raw material of following mass percent：Activity
Ester Polyethylene Glycol maleimide 20% and Polyamide amine 5%, balance of water.
The molecular weight of the active ester Polyethylene Glycol maleimide is 5000Da.
Described Polyamide amine is three generations's dendrimer.
The pH of the injection aquagel is 7.4.
Embodiment 4
Based on the injection aquagel of an one-step physical chemical method plastic, it is made up of the raw material of following mass percent：Activity
Ester Polyethylene Glycol maleimide 15% and Polyamide amine 5%, balance of water.
The molecular weight of the active ester Polyethylene Glycol maleimide is 5000Da.
Described Polyamide amine is three generations's dendrimer.
The pH of the injection aquagel is 7.5.
Embodiment 5
Based on the injection aquagel of an one-step physical chemical method plastic, it is made up of the raw material of following mass percent：Activity
Ester Polyethylene Glycol maleimide 10% and Polyamide amine 5%, balance of water.
The molecular weight of the active ester Polyethylene Glycol maleimide is 5000Da.
Described Polyamide amine is three generations's dendrimer.
The pH of the injection aquagel is 6.
Embodiment 6
The present embodiment is the preparation method of the injection aquagel of embodiment 1, comprises the following steps：
A, the phosphorus that active ester Polyethylene Glycol maleimide and Polyamide amine are dissolved in pH 7.2 at room temperature respectively
In phthalate buffer, active ester Polyethylene Glycol maleimide is formulated as into the solution of 100g/L, Polyamide amine is formulated as
The solution of 100g/L.
B, the active ester Polyethylene Glycol maleimide amine aqueous solution that step A is obtained and polyamide-based amine aqueous solution are by 1：1 volume
Mixing, obtains hydrogel.
Embodiment 7
The present embodiment is the preparation method of the injection aquagel of embodiment 2, comprises the following steps：
A, the phosphorus that active ester Polyethylene Glycol maleimide and Polyamide amine are dissolved in pH 7.5 at room temperature respectively
In phthalate buffer, Polyamide amine is formulated as into the solution of 100g/L, active ester Polyethylene Glycol maleimide is formulated as
The solution of 700g/L.
B, the active ester Polyethylene Glycol maleimide amine aqueous solution that step A is obtained and polyamide-based amine aqueous solution are by 1:1 volume
Mixing, obtains hydrogel.
Embodiment 8
The present embodiment is the preparation method of the injection aquagel of embodiment 3, comprises the following steps：
A, the phosphorus that active ester Polyethylene Glycol maleimide and Polyamide amine are dissolved in pH 7.4 at room temperature respectively
In phthalate buffer, Polyamide amine is formulated as into the solution of 100g/L, active ester Polyethylene Glycol maleimide is formulated as
The solution of 400g/L.
B, the active ester Polyethylene Glycol maleimide amine aqueous solution that step A is obtained and polyamide-based amine aqueous solution are by 1:1 volume
Mixing, obtains hydrogel.
Control experiment
The present invention selects the PAMAM and NHS-PEG5000-MAL of three generations (G3) as model element A and B.
Experiment condition：Mix the PAMAM and 400g/L of 100g/L under room temperature in the phosphate buffer (PBS) of pH 7.4
NHS-PEG-MAL (mass ratio is 1:4) 25%w/v gels are obtained.
Reference substance：Using (A groups) maleimide Polyethylene Glycol methoxyl group (MAL- that identical PEG molecular weight is 5000Da
) and PAMAM, (B groups) N-hydroxy-succinamide Polyethylene Glycol methoxyl group (NHS-PEG-OMe) and PAMAM, (C groups) PEG-OMe
MAL-PEG-MAL and PAMAM, (D groups) NHS-PEG-NHS and PAMAM are used as control.
As a result：There is no gelation in the mixed solution of A groups and B groups；And C groups, D groups and NHS-PEG-MAL are within a few minutes
Stable hydrogel is formed with PAMAM.
As can be seen here, the PEG with single one physical (only MAL) or chemical (only NHS) crosslink sites can not be formed with PAMAM
Hydrogel.Conversely, if it has two crosslink sites, two MAL or two NHS can form stable water with PAMAM
Gel.Show that the pure physical crosslinking based on MAL and the pure chemistry crosslinking based on NHS can form hydrogel with PAMAM.This
Outward, the feasibility of our step gelation process is forcefully demonstrated based on the formation of the hydrogel of NHS-PEG-MAL, and is led to
Cross following driving force to realize：Based on NHS and NH2Ester interchange, MAL and NH2Hydrogen bond action, and on NHS-PEG-PEG
MAL groups between non-covalent π-π superpositions.
Spectrum analyses
In order to confirm the hydrogen bond action between two model elements, Fourier transform infrared (FT-IR) spectrum analyses are carried out.
As shown in figure 1, the α of the MAL groups on NHS-PEG-MAL, the stretching vibration of alpha, beta-unsaturated ketone carbonyl (- C=O) is in 1720cm-1
Place is with typical absorption band.However, NHS-PEG-MAL and variable concentrations as 10g/L PAMAM (100g/L, 400g/L and
When 700g/L) forming gel, 1720cm-1Place's absorption intensity is significantly reduced, and shows the ketone carbonyl on MAL and the NH on PAMAM2It
Between there is hydrogen bond action.
Additionally, carbon-to-carbon double bond (- C=C) is in 1650cm-1The typical stretching vibration absorption intensity at place it is constant, further demonstrate,prove
It is real to be based on MAL and NH2Interaction be hydrogen bond rather than other chemical actions, such as Michael's addition.0.1%w/v
The UV-vis spectrum of PAMAM, MAL-PEG-MAL and MAL-PEG-MAL/PAMAM aqueous solution can further verify the conclusion.
As shown in Fig. 2 PAMAM is as its saturated alkane structure is without characteristic absorption band, MAL-PEG-MAL is at 290nm
Characteristic absorption peak is derived from what π π (C=C) and the chromophoric conjugations of n π (C=O) on MAL groups were excited.With PAMAM's
Add, its absorption intensity significantly increases and further demonstrates that MAL and NH with obvious blue shift (moving to 250nm from 290)2
Between there is no Michael addition reaction.Therefore, these results further demonstrate that MAL and NH2Between hydrogen bond action presence.
(25%w/v, by mixing 100g/L PAMAM and 400g/L MAL-PEG- for MAL-PEG-MAL/PAMAM hydrogels
MAL) excellent pH sensitivity and reversibility also demonstrate that MAL and NH2Between hydrogen bond action.As shown in figure 3, MAL-PEG-
MAL/PAMAM hydrogels can only be formed under neutrallty condition (pH6～8).In acid condition (i.e. pH<6) under, NH2Easily protonate
And form corresponding ammonium ion (NH3 +), cause MAL and NH2Hydrogen bond action between group is reduced and is even disappeared, it is difficult to plastic；
In alkalescence condition (i.e. pH>8), under, the slow hydrolysis of MAL groups is likely to hinder the formation of hydrogen bond and hydrogel.
In addition to ester exchange and hydrogen bond action, non-covalent π-π superpositions have also assisted in the formation of one-step physical chemistry hydrogel,
This conclusion may certify that by the formation of 4arm-PEG-MAL hydrogels.In this system, MAL groups are unique crosslinkings
Site, its non-covalent π-π superposition is the unique driving force to form hydrogel.For proving this conclusion, tracked in 48 hours
The UV-vis spectrum of 4arm-PEG-MAL aqueous solutions (0.1%w/v).As shown in figure 4, due to the non-covalent π-π superpositions of MAL groups
Effect, its feature chromophore intensity at 290nm gradually increase with the passage of time.And it is of note that 25%w/v
4arm-PEG-MAL hydrogels gelation time (about 12 hours) considerably longer than than the present invention one-step method hydrogel it is solidifying
The glue time (about tens seconds to a few minutes), show that non-covalent π-π stackings are relatively weak driving forces, can lentamente participate in 3D nets
Network gradually improves process.
It is to form one-step physical chemistry water-setting that Fig. 1-Fig. 4 fully demonstrates ester exchange, hydrogen bond action and non-covalent π-π superposition
The main drive of glue.In addition, it has also been found that the algebraically of the molecular weight and PAMAM of other factors, such as PEG can also show
Writing affects the formation of hydrogel.As shown in figure 5, NHS-PEG-MAL of the PEG molecular weight less than 5000Da (i.e. 2000 and 3500Da)
Hydrogel can not be formed with the PAMAM in 3 generations under any concentration and any mol ratio.Similarly, when PAMAM algebraically is less than three
Gelation can not occur with NHS-PEG5000-MAL under any concentration and any mol ratio during generation (i.e. G2).PEG molecular weight
Dependency gelation behavior may be related to the chain length of PEG and flexibility.Because the PEG pliabilities of low-molecular-weight are poor, segment
It is shorter, it is impossible to by PAMAM molecule cross-links together；Additionally, PAMAM algebraically dependency gelation behaviors are attributable to different algebraically
The difference of the surface texture of PAMAM and rigidity.Low PAMAM is rigidly poor for algebraically, and dendritic structure stacking glue is loose, is unfavorable for
Plastic.
In a word, the above results demonstrate the feasibility of a step gelation of the present invention, and this hydrogel can be by two kinds often
See, simultaneous physics (hydrogen bond between widely used and business-like plastic unit (PAMAM and NHS-PEG-MAL)
Stack with π-π) and chemistry (ester exchange) crosslinked action realizing.This knot further demonstrate that by the microstructure of hydrogel
By.As shown in fig. 6, the TEM photos of 25%w/v hydrogels show which has the dendroid of uniform and diameter about 500nm crosslinking knot
Structure, this dendritic nanostructured are indicated between PAMAM and NHS-PEG-MAL well by the nanosphere in PAMAM
The ester interchange occurred on shape body structure surface, hydrogen bond action and π-π stackings interact entangled.This dendritic morphology
Also also once it was observed in previous studies.
Performance Evaluation
After the step gelation process for setting up this novelty, the present invention have evaluated the water by following experimental system
The uniformity of controllability and hydrogel of the gel in terms of porosity, gelation rate, mechanical strength, plasticity and cell toxicant
Property.
1st, electron microscope scanning
Using SEM observe an one-step physical chemistry hydrogel external morphology, by 100g/L PAMAM respectively with different quality
NHS-PEG-MAL mixing (the PAMAM of concentration (100g/L, 400g/L and 700g/L):NHS-PEG-MAL=1/1,1/4 and 1/7)
Prepare 10%, 25% and 40%w/v hydrogel.As shown in Figure 7 A, the section of three kinds of lyophilizing hydrogels all presents continuously
Loose structure, porosity gradually increase with the increase of gel strength.The one one-step physical chemistry hydrogel of the present invention is except in hole
Have in terms of porosity outside good controllability, also the homogeneity with height, the 25%w/v hydrogels of for example fresh preparation of its result
Laser Scanning Confocal Microscope photo shown in (Fig. 7 B).The uniform loose structure of the hydrogel gives their plurality of advantages, such as can conduct
Various bioactive molecules are delivered or for cell encapsulating and the ideal carrier cultivated or support.Additionally, there are some researches show water-setting
The height homogeneity of glue is conducive to the mechanical strength of raising hydrogel and is that cell adhesion and propagation provide more suitably framework.
2nd, rheology testing
Gelation rate and the mechanical performance of hydrogel are measured using dynamic rheometer, as shown in Figure 8.In Fig. 8 A1, water-setting
The gelation time (G' and G " between the corresponding abscissa in cross point) of glue shows the high dependency to gel strength.It is logical
Cross and gel strength is adjusted to 10%w/v from 40%, gelation time is corresponding to be changed into a few minutes from tens seconds, indicated gelling
The excellent controllability of time, this is that water-setting gathers a most basic and most important prerequisite for in-situ injection.Additionally, this
Minimum gelation concentration (MGC) of class hydrogel is 10%w/v.It is interesting that the storage moduluss (G') of such hydrogel also have
There is the high dependency of gel strength, increase to 40%w/v with gel strength from 10%, G' increases sharply 1MPa from 400Pa.Value
Obtain it is noted that the storage moduluss (1MPa) of 40%w/v hydrogels are significantly higher than most of physical hydrogels of current report.Frequently
Rate scanning experiment further demonstrate that the machinery of the good controllability and 40%w/v hydrogel superelevation of such hydrogel mechanical strength
Intensity (Fig. 8 A2).As shown in Fig. 8 A3, when stress is less than or equal to 100%, " value keeps permanent for the G' and G of 40%w/v hydrogels
Fixed, when strain reaches more than 1000%, " value starts quick reduction for G' and G.Result above shows the water-setting that a step gel method is formed
Glue in the case where the destruction of sizable external force is born can holding structure integrity, and this survivability is with hydrogel concentration
Increase.This excellent mechanical strength complies fully with the expectation of medicine delivery and organizational project application, because hydrogel is applied
Need to bear the environmental change caused by external mechanical load during these fields, in addition it is also necessary to resist the high pressure in damage field to keep away
Exempt from the bioactive molecule that contains or the prominent of cell is released.
Outside the homogeneity of height, and the excellent controllability of porosity, gel time and mechanical performance, the water of the present invention
Gel also has excellent plasticity.As shown in Figure 8 B, hydrogel can be formed it is desirable that it is variously-shaped, such as it is square
Shape, circular, rhombus and triangle, illustrate can by the precursor solution of gel be injected directly in the lesion region of complicated shape with
Realize gel process in situ and minimally invasive.
As described above, a step gel method and traditional physics of the present invention, chemical to compare tool with order multistep cross-linking strategies
Have many advantages, such as, including excellent mechanical performance, good homogeneity and plasticity, and in gelation rate, porosity and
The excellent controllability of the aspects such as mechanical performance.This high controllability may come from the definitiveness of crosslink sites, participate in crosslinking
Functional group number purpose accuracy, and the accuracy controlling of two kinds of gel cell concentration.
3. cytotoxicity detection
It is well known that hindering one of widely used major reason of injection aquagel to be that gelatinizing-in-situ process causes
Cytotoxicity.Therefore, the present invention detects the cytotoxicity of our step gelation processes by live/dead cell dyeing.This
Bright direct HeLa cells and the fibroblastic surface in situ plastics of Mus source NIH 3T3 in drawout.And with phase homogeneity
The pure chemistry based on NHS-PEG-NHS and MAL-PEG-MAL of amount fraction (25%w/v) and physical gel are control material.
After incubation 24 hours, visible a large amount of dead cells in the pure chemistry hydrogel based on NHS-PEG-NHS, this is probably
Caused due to their relatively quick gelation processes.By contrast, in the pure physical hydrogel based on MAL-PEG-MAL and
Almost without dead cell in the one one-step physical chemistry hydrogel of the present invention, show that a step gelation process of the present invention has temperature relatively
With the gelation process of safety.This is the prerequisite that injection aquagel is applied to in-situ injection.The result shows this
The one one-step physical chemistry hydrogel of invention has huge diving in various biomedical applications (such as situ drug induction system)
Power.
The present invention is further by 105Individual HeLa cells and NIH 3T3 fibroblasts are directly mixed with hydrogel premise solution
Share and be encapsulated with the hydrogel of cell in preparing, and carry out after cultivating 12,24 and 48 hours respectively live/dead cell dyeing and
CCK8 is detected.The HeLa cells and NIH3T3 fibroblasts being encapsulated in 25%w/v hydrogels was presented in 12 to 48 hours
Good growth tendency, and it is observed that good stretching spindle shape morphology after plastic 24 hours.CCK8 results also table
Bright, the cell in all hydrogels all keeps good activity, for example, 10%, in 25% and 40%w/v hydrogel, HeLa is thin
The cell survival rate of born of the same parents (Fig. 9 A1) respectively reaches 94%, 85% and 82%, slightly above NIH 3T3 cells about 92%, 86% and
77% (Fig. 9 A2).It is gentle safety that these results are further characterized by a step gelation process of the present invention, and with good
Biocompatibility, it is that cell growth and increment are provided that this may be attributed to the suitable porosity of such hydrogel and mechanical strength
Preferable microenvironment.
Therefore, an one-step physical of the invention chemistry hydrogel has huge application potential, is such as used in regenerative medicine
Cell is encapsulated, even serving as the bio-ink of 3D biometric prints.Additionally, PAMAM unique nanometer chondritic not only can be carried
It is used for encapsulating various bioactive molecules or medicine for big inner chamber, but also abundant periphery NH is provided2Group is used for carrying
Or the various medicines of chemical bonding or treatment molecule (i.e. photosensitizer, CO/NO release molecules) are used for chemotherapy, photodynamic therapy
(PDT), Gases for Treating, and multi-medicament therapeutic alliance.
To sum up, the invention provides a kind of combine physics with chemical crosslinking for preparing while injection aquagel
One step gelation process, the method are prepared super easy and have multifunctionality.It is due to the crosslink sites which determines, accurate to be crosslinked
Group numbers, and the exact controllability of two kinds of gellings unit concentration (NHS-PEG-MAL and PAMAM), the method is not only solidifying
Gel speed, porosity and mechanical properties show excellent controllability, also exhibit improvements over many of conventional hydrogels
Advantage, such as excellent mechanical performance, good homogeneity, plasticity and biocompatibility.Additionally, the major lumen inside PAMAM
With abundant peripheral NH2Give obtained hydrogel and there is multi-functional so as to joint multiple therapy methods can be become
Platform.
Claims (6)
1. a kind of injection aquagel based on an one-step physical chemical method plastic, it is characterised in that by following mass percent
Raw material is constituted：Active ester Polyethylene Glycol maleimide 5-35% and Polyamide amine 5%, balance of water.
2. the injection aquagel based on an one-step physical chemical method plastic according to claim 1, it is characterised in that described
Active ester Polyethylene Glycol maleimide is 1～7 with the mass ratio of Polyamide amine:1.
3. the injection aquagel based on an one-step physical chemical method plastic according to claim 1, it is characterised in that described
The molecular weight of active ester Polyethylene Glycol maleimide is 5000Da.
4. the injection aquagel based on an one-step physical chemical method plastic according to claim 1, it is characterised in that described
Polyamide amine be three generations's dendrimer.
5. the injection aquagel based on an one-step physical chemical method plastic according to claim 1, it is characterised in that this can
The pH of injection hydrogel is 6～8.
6. according to claim 1-5 any one based on an one-step physical chemical method plastic injection aquagel preparation side
Method, it is characterised in that active ester Polyethylene Glycol maleimide and Polyamide amine are dissolved in pH respectively at room temperature is
In the phosphate buffer of 7.2-7.5, then it is mixed in proportion, obtains hydrogel.
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