CN105597156B - Hydrogel and its preparation method and application - Google Patents
Hydrogel and its preparation method and application Download PDFInfo
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Abstract
A kind of hydrogel, it includes containing liposome, the biology of the compatible metal ion of biology to use high molecular material and water, the liposome can be cross-linked with each other with the biology with high molecular material, the biology can be 10 ~ 49% with the percentage by volume of high molecular material, the percentage by volume of the liposome for containing the compatible metal ion of biology is 5 ~ 49%, and the percentage by volume of the water is 2 ~ 85%.A kind of preparation method of hydrogel and its application.The compatible metal ion of biology contained in hydrogel of the invention can fetter formation and performance that liposome adjusts gel.The hydrogel can be after being injected into human body, and specific release metal ions inspire high molecular crosslink and form network structure at 37 DEG C of body temperature, can change rapid gellation by perception body temperature, have preferable temperature-sensing property.
Description
Technical field
The present invention relates to biomedical materials fields, more particularly to a kind of hydrogel and its preparation method and application.
Background technique
Hydrogel has tridimensional network and certain mechanical properties, is cytotrophy substance, oxygen and metabolite
It conveys and the good transport channel of offer is provided, while building three dimensional growth environment for cell, part hydrogel still has promotion
New vessels form equal biophysical properties, therefore hydrogel has certain advantage in terms of as cell carrier, such as
It can be used as the material of plastotype bracket.
Conventional hydrogels bracket is mostly external preparatory plastotype, is then implanted by way of operation to internal pre-determined bit
Set, however since human body defective tissue or organ normally shape are very irregular, the shape of timbering material often with target site
It can not fit like a glove, and be difficult to avoid to cause the secondary insult to patient in surgical procedure.
Summary of the invention
In view of this, the present invention provide it is a kind of can after being injected in vivo gelation hydrogel.
A kind of hydrogel comprising biology can with high molecular material, contain the liposome of the compatible metal ion of biology
And water, the liposome can be cross-linked with each other with the biology with high molecular material, wherein biology can use the volume of high molecular material
Percentage is 10~49%, and the percentage by volume of the liposome for containing the compatible metal ion of biology is 5~49%, institute
The percentage by volume for stating water is 2~85%, and the biology can include natural macromolecular material, active aldehyde with high molecular material
In the high molecular material of the high molecular material of base, the high molecular material with bio-ligand and active aldehyde radical and bio-ligand
Two or more, the natural macromolecular material includes that alginic acid, hyaluronic acid, chondroitin sulfate, collagen, shell are poly-
One of sugar, gelatin, fibroin albumen, keratoprotein, starch, polypeptide and its salt are a variety of, and the bio-ligand includes hydrochloric acid
One or both of dopamine and mussel attachment proteins, the compatible metal ion of biology includes Na+、K+、Ca2+、Fe3+、
Zn2+And Mn3+One or more of.
A kind of preparation method of above-mentioned hydrogel, includes the following steps：
Preparation contains the liposome of the compatible metal ion of biology；
The liposome for containing the compatible metal ion of biology can be added in the solvent of high molecular material to containing biology
And be uniformly mixed, mixed liquor is obtained, the biology can include natural macromolecular material, active aldehyde radical with high molecular material
Two in the high molecular material of high molecular material, the high molecular material with bio-ligand and active aldehyde radical and bio-ligand
Kind or it is two or more, the natural macromolecular material includes alginic acid, hyaluronic acid, chondroitin sulfate, collagen, chitosan, bright
One of glue, fibroin albumen, keratoprotein, starch, polypeptide and its salt are a variety of, and the bio-ligand includes Dopamine hydrochloride
One or both of with mussel attachment proteins, the compatible metal ion of biology includes Na+、K+、Ca2+、Fe3+、Zn2+With
Mn3+One or more of；
By mixed liquor temperature reaction, hydrogel is obtained.
A kind of hydrogel is as the application in biological organization material.
The compatible metal ion of biology contained in hydrogel of the invention, can fetter the formation that liposome adjusts gel
And performance.The hydrogel can be after being injected into human body, and specific release metal ions inspire high molecular crosslink at 37 DEG C of body temperature
Network structure is formed, rapid gellation can be changed by perception body temperature, there is preferable temperature-sensing property.Therefore,
Hydrogel of the invention can be used Minimally Invasive Surgery and be injected directly into demand position, according to the variation of temperature gel in-situ in vivo,
The molding of individuation shape is adapted to, overcoming the external preformed of conventional hydrogels, the shape of timbering material and target site cannot be complete
The problems such as coincideing, avoids the secondary insult of patient.
Detailed description of the invention
The hydrogel Thermo-sensitive dynamics schematic diagram of the active aldehyde radical of Fig. 1 and bio-ligand.
The preparation flow schematic diagram of the hydrogel of the active aldehyde radical of Fig. 2 and bio-ligand.
Main element symbol description
| Contain the liposome of the compatible metal ion of biology | 100 |
| The high molecular material of active aldehyde radical and bio-ligand | 200 |
| The hydrogel of active aldehyde radical and bio-ligand | 300 |
| Natural macromolecular material | 400 |
| The high molecular material of active aldehyde radical | 500 |
| Bio-ligand | 600 |
| Mixed liquor | 700 |
The present invention that the following detailed description will be further explained with reference to the above drawings.
Specific embodiment
A kind of hydrogel that the present invention protects comprising biology can with high molecular material, contain the compatible metal of biology
The liposome and water of ion, the liposome can be cross-linked with each other with the biology with high molecular material, and the biology can use high score
The percentage by volume of sub- material is 10~49%, wherein containing the percentage by volume of the liposome of the compatible metal ion of biology
It is 5~49%, the percentage by volume of the water is 2~85%.
Liposome in the above-mentioned liposome for containing the compatible metal ion of biology includes but is not limited to two palmityl phosphorus
Ester phatidylcholine (Dipalmitoyl phosphatidyl choline, DPPC), dimyristoyl phosphatidyl choline (1,2-
Dimyristoyl-sn-glycero-3-phosphocholine, DMPC), two myristoyl trimethyl ammonium propanes (1,2-
Dimyristoyl-3-trimethylammonium propane, DMTAP) and Distearoyl Phosphatidylcholine (Distearoyl
Phosphatidylcholine, DSPC) one of or it is a variety of.
The compatible metal ion of biology is the metal ion that bioabsorbable can't cause damages.Including but not
It is limited to and preferable 1 valence of human-body biological compatibility, divalent or trivalent metal ion, especially sodium ion (Na+), potassium ion (K+)、
Calcium ion (Ca2+), iron ion (Fe3+), zinc ion (Zn2+) and manganese ion (Mn3+) one of or it is a variety of.
Hydrogel in the prior art is more to solidify in vitro or is formed cross-linked structure, can only be transplanted again by external plasticity
Enter in vivo.The compatible metal ion of biology that hydrogel of the invention contains can fetter formation and property that liposome adjusts gel
Energy.The hydrogel can be after being injected into human body, and specific release metal ions inspire high molecular crosslink and formed at 37 DEG C of body temperature
Network structure can change rapid gellation by perception body temperature, have preferable temperature sensitivity, i.e., temperature sensitive
Property.Therefore, hydrogel of the invention can be used Minimally Invasive Surgery and be injected directly into demand position, former in vivo according to the variation of temperature
Position plastic adapts to the molding of individuation shape, overcomes the external preformed of conventional hydrogels, the shape of timbering material and target site not
The problems such as capable of fitting like a glove, avoids the secondary insult of patient.
Further, the biology can include the high score of natural macromolecular material, active aldehyde radical with high molecular material
Two kinds in the high molecular material of sub- material, the high molecular material with bio-ligand and active aldehyde radical and bio-ligand or
It is two or more.
Above-mentioned bio-ligand includes but is not limited to the one or more of Dopamine hydrochloride and mussel attachment proteins, especially salt
Sour dopamine (Dopamine Hydrochloride, DOPA), Perna viridis byssus protein (Perna viridis foot
Protein, Pvfp) and one of mussel attachment proteins (mussel adhesive protein, MAP) or a variety of.Wherein
MAP includes but is not limited to Trachyostracous mussel byssus protein 1 (Mytilus coruscus foot protein 1, McfP1), thick shell
Mussel byssus protein 2 (McfP2), Trachyostracous mussel byssus protein 3 (McfP3), Trachyostracous mussel byssus protein 4 (McfP4), thick shell are made a gift of
One of byssus albumen 5 (McfP5) and Trachyostracous mussel byssus protein 6 (McfP6) are a variety of.Preferably McfP3, McfP4,
One of McfP5 or a variety of.The bio-ligand contains more Dopamine hydrochloride (DOPA) and hydroxyproline
(hydroxyproline, Hyp) can form very strong hydrogen bond with the protein isopolarity polymer in biological tissue, have
Stronger adhesion activity.
Above-mentioned natural macromolecular material includes but is not limited to the one or more of polysaccharide, protein and its salt.It is especially extra large
In alginic acid, hyaluronic acid, chondroitin sulfate, collagen, chitosan, gelatin, fibroin albumen, keratoprotein, starch, polypeptide and its salt
It is one or more.The polysaccharide, protein and its salt all have good human-body biological compatibility.
Therefore the hydrogel that in the present invention prepared by the high molecular material with bio-ligand, adhesion property with super strength,
With the liposome for containing the compatible metal ion of biology chelation occurs for the bio-ligand contained in hydrogel, carries out chemistry
Crosslinking, forms the structure of interpenetrating networks, further strengthens the stability and adhesiveness of hydrogel, realize the chemistry under hygrometric state
Dynamic self-repair function, and then extend the service life of hydrogel in vivo, improve the delay and activity of cell in vivo.
In addition, the aldehyde radical in the present invention in the hydrogel of the high molecular material preparation of active aldehyde radical can be with tissue egg
The hydrogel that schiff base reaction forms covalent cross-linking occurs for the amino in the amino and other natural macromolecular materials in white, improves
The mechanical property and cellular affinity of hydrogel.
Further, the hydrogel of the high molecular material of active aldehyde radical and bio-ligand preparation has simultaneously in the present invention
The characteristics of standby syringeability, Thermo-sensitive and self-healing property, be a kind of temperature sensitive self-healing property multifunctional water gel of new injectable, temperature sensitive
Property dynamics schematic diagram as shown in Figure 1, the compatible metal ion of biology and liposome generates in vitro contain it is biological compatible
The liposome 100 of metal ion, then active aldehyde is generated with the high molecular material 200 of active aldehyde radical and bio-ligand
The hydrogel 300 of base and bio-ligand, specific release metal ions inspire high molecular crosslink shape to the hydrogel at 37 DEG C in vivo
At network structure.The principle of hydrogel mimic biology bulk damage healing, material once generates defect, in the feelings of no external influence
Under condition, the self-healing of micro-crack is realized.This function is able to extend the service life of material in vivo.
Further, the hydrogel in the present invention is all made of the natural material preparation with good biological compatibility,
With excellent biological compatibility, degradation property, special cytosis site.
Invention further provides the preparation methods of above-mentioned hydrogel, include the following steps：
1, preparation contains the liposome of the compatible metal ion of biology；
In above-mentioned preparation method, the liposome that the preparation contains the compatible metal ion of biology is made as follows
At：Liposome compound is dissolved in organic solvent, the aqueous solution containing the compatible metal ion of biology is added, is uniformly mixed,
Obtain containing the liposome of the compatible metal ion of biology.
The organic solvent includes but is not limited to one or more of methylene chloride and chloroform.
The liposome compound be dissolved in the concentration after organic solvent be 1~500mg/mL, 1~400mg/mL, 1~
300mg/mL, 1~200mg/mL, 1~100mg/mL or 1~50mg/mL.
Further, the organic solution of liposome compound can be also made to dried object, method can use any
The common method of field technical staff, for example, heating, vacuum drying etc..Present invention preferably employs the methods of revolving, by liposome
Liposome membrane is made in compound organic solution.Rotating temperature is 20~70 DEG C, and revolving speed is 50~200rpm.
The concentration of the aqueous solution of the compatible metal ion of biology is 0.1~25mol/L, 0.1~20mol/L, 0.1
~15mol/L, 0.1~10mol/L, 0.1~5mol/L or 0.1~2.5mol/L.
Further, to promote liposome sufficiently to react with metal ion, it can be warming up to certain temperature in the reaction, this temperature
Preferably 40~80 DEG C of degree.Further, reaction system can also be placed in ultrasound in ultrasonic generator, until liquid-transparent.
Preferably, ultrasonic temperature is 40~80 DEG C, and the diameter of ultrasonic probe is 2~5mm, and ultrasonic time is 10~120min, ultrasound
Power be 50~200w.
If having heating when reaction, to the end of reacting, mixed solution can be cooled to room temperature.
It will be appreciated by those skilled in the art that, it further can also include purifying, dry after fully reacting.Purifying
Method can use the common method of anyone skilled in the art, for example, filtering, washing, centrifugation etc..The present invention preferably adopts
Extra metal ion is removed with centrifugation, centrifugal force is 1000~30000g.Sediment is dissolved in alcohol organic solvent again, it is excellent
It is selected as ethyl alcohol, concentration is 2~8mol/L, obtains white suspension.White suspension is passed through nitrogen, removal alcohols is organic molten
Agent.Finally with etc. infiltration brine, centrifugation, this step it is recyclable multiple.The grade permeates physiological saline formula：
10mol/L 4- hydroxyethyl piperazineethanesulfonic acid (4- (2-hydroxyerhyl) piperazine-1-erhaesulfonic acid,
HEPES), 1mmol/L disodium ethylene diamine tetraacetate (Ethylenediaminetetraacetic acid disodium salt,
EDTA), the sodium chloride that concentration is 0.9%, pH value 7.4.
The dry method for containing the liposome of the compatible metal ion of biology that is made preferably is freeze-dried.
2, the lipid for containing the compatible metal ion of biology can be added in the solvent of high molecular material to containing biology
Body is simultaneously uniformly mixed, and obtains mixed liquor；
The biology can include natural macromolecular material, the high molecular material of active aldehyde radical, tool with high molecular material
There is two or more in the high molecular material of bio-ligand and the high molecular material of active aldehyde radical and bio-ligand.
The natural macromolecular material include but is not limited to alginic acid, hyaluronic acid, chondroitin sulfate, collagen, chitosan,
One of gelatin, fibroin albumen, keratoprotein, starch, polypeptide and its salt are a variety of.
Further, the high molecular material of the active aldehyde radical is made as follows：By natural polymer material
Material is dissolved in solvent, and oxidant is added and carries out oxidation reaction, obtains active aldehyde radical high molecular material.It further, will be natural
High molecular material oxidation can be selected oxidant well-known to those skilled in the art, for example, potassium chlorate, chromium trioxide, hydrogen peroxide,
Sodium metaperiodate etc., preferably sodium metaperiodate.
In the particular embodiment, different natural macromolecular materials should be dissolved in different solvents.Such as it is molten with organic acid
Solve chitosan, fibroin albumen, keratoprotein, collagen, polypeptide etc..With water dissolve hyaluronic acid or its salt, alginic acid or its
Salt, starch, chondroitin sulfate or its salt etc..The organic acid is preferably acetic acid or malonic acid.
Further, until reaction a period of time, can also be added a certain amount of ethylene glycol and terminate reaction.Those skilled in the art
Product is isolated and purified it should be understood that the common method of anyone skilled in the art can be used after reaction, is removed
Impurity dialyses for example, by using the bag filter of certain molecular weight, chromatographic isolation or ultrafiltration membrane etc. can also be used.It is preferred that bag filter used
Molecular weight be 3000~8000Da.
Further, it can also be dried after isolating and purifying, preferably freeze drying, the high score of active aldehyde radical is made
Sub- material.The freeze-drying is to freeze 2h under subzero 40~90 DEG C of ultralow temperature, is put into freeze drier after freezing, zero
It is freeze-dried for 24 hours under the conditions of 50~60 DEG C lower.
The concentration that above-mentioned natural macromolecular material is dissolved in solvent is 0.2~1wt%, and the concentration of preferably clear matter hydrochlorate is
0.01~1%wt%, molecular weight are 1.0 × 104~1.5 × 106Da.The amount of above-mentioned addition oxidant is natural macromolecular material
It is added 0.1~10 times of mole, the reaction time is 0.5~12h.The mole that ethylene glycol is added is sodium metaperiodate mole
1~5 times.
Further, the macromolecule of the high molecular material or active aldehyde radical and bio-ligand with bio-ligand
Material is made as follows：The high molecular material of natural macromolecular material or active aldehyde radical is dissolved in solvent, is adjusted
PH is saved, nitrogen is passed through, adds bio-ligand, be protected from light, obtain the high molecular material with bio-ligand or active
The high molecular material of aldehyde radical and bio-ligand.
The high molecular material of above-mentioned different active aldehyde radical should be dissolved in different solvents.Such as have with organic acid dissolution
Chitosan, fibroin albumen, keratoprotein, collagen, polypeptide of active aldehyde radical etc.；The saturating of active aldehyde radical is dissolved with water
Bright matter acid or its salt, alginic acid or its salt, chondroitin sulfate or its salt, starch etc..The organic acid is preferably acetic acid or the third two
Acid.The method that different natural macromolecular materials is dissolved in solvent is as previously described.
Further, carboxyl activator can also be added, such as carbodiimides (Carbodiimide, EDC) and N- hydroxy benzenes
And the one or more of triazole (NHydroxybenzotrizole, HOBt), increase natural macromolecular material or active
The high molecular material of aldehyde radical reacts incidence with bio-ligand.N- hydroxysuccinimide (N- can also further be added
Hydroxysuccinimide, abbreviation NHS) reduce side reaction.
It will be appreciated by those skilled in the art that, the method for adjusting pH can be used what those skilled in the art generallyd use
Method, such as adjusted with certain density sodium hydroxide or hydrochloric acid.
It will be appreciated by those skilled in the art that, anyone skilled in the art commonly side also can be used after reaction
Method isolates and purifies, and removes impurity, dialyses for example, by using the bag filter of certain molecular weight, chromatographic isolation or ultrafiltration membrane can also be used
Deng.It is preferred that the molecular weight of bag filter used is 3000~8000Da.
Further, it can also be dried after isolating and purifying, preferably freeze drying, the high score with bio-ligand is made
Sub- material.The freeze-drying is to freeze 2h under subzero 40~90 DEG C of ultralow temperature, is put into freeze drier after freezing, zero
It is freeze-dried for 24 hours under the conditions of 50~60 DEG C lower.
Further, the bio-ligand is in Dopamine hydrochloride, Perna viridis keratoprotein and mussel attachment proteins
It is one or more.Further, the mussel attachment proteins are in McfP1, McfP2, McfP3, McfP4, McfP5 and McfP6
It is one or more.Preferably one of McfP3, McfP4, McfP5 or a variety of.
When the concentration of natural macromolecular material or the solution of the high molecular material of active aldehyde radical is 0.2~1wt%,
The amount of dehydrating agent is 2 times of the high molecular material of natural macromolecular material or active aldehyde radical, if the additional amount of EDC is polymerization
2 times of object mole, and the additional amount of NHS is mole is added in EDC 2 times.The pH adjusting agent of above-mentioned addition such as sodium hydroxide
Concentration be 1~5mol/L or hydrochloric acid concentration 0.5-2mol/L, pH value is 3~6.
The amount of the bio-ligand of the addition is different according to the molecular weight of bio-ligand.Such as the additional amount of DOPA
It is 0.1~10 times of the high molecular material mole of natural macromolecular material or active aldehyde radical；The additional amount of Pvfp is day
0.1~5 times of the mole of the high molecular material of right high molecular material or active aldehyde radical；McfP-3,McfP-4,McfP-5
Additional amount be 0.1~8 times of high molecular material mole of natural macromolecular material or active aldehyde radical.It is protected from light
Time be 1~for 24 hours.
It will be appreciated by those skilled in the art that, the high molecular material and life of natural macromolecular material or active aldehyde radical
The mixing of object ligand, and do not limited with the sequencing that metal ion liposome mixes is contained.For example, in specific embodiment
In, can first by the high molecular material and bio-ligand of natural macromolecular material or active aldehyde radical mix, then with contain biology
The liposome of compatible metal ion mixes.It can also be first by natural macromolecular material or the high molecular material of active aldehyde radical
It mixes with the liposome for containing the compatible metal ion of biology, then is mixed with bio-ligand.It can also be first by part natural polymer
The high molecular material of sub- material or active aldehyde radical and the liposome mixing for containing the compatible metal ion of biology, then with it is surplus
Remaining part divides the high molecular material of natural macromolecular material or active aldehyde radical, bio-ligand mixing.
Further, by with bio-ligand high molecular material and the liposome that contains the compatible metal ion of biology
Mixing, first can be dissolved in solvent for the high molecular material with bio-ligand.The different high molecular materials with bio-ligand are answered
It is dissolved in different solvents, such as there is chitosan, fibroin albumen, keratoprotein, the collagen egg of bio-ligand with organic acid dissolution
White, polypeptide etc.；With water dissolution have bio-ligand hyaluronic acid or its salt, alginic acid or its salt, chondroitin sulfate or its salt,
Starch etc..The organic acid is preferably acetic acid or malonic acid.Similarly, the macromolecule of natural macromolecular material and active aldehyde radical
The configuration of the solution of material is as previously described.
Further, into the solvent that can use high molecular material containing biology, containing biology by preset ratio addition can be simultaneous
The liposome of the metal ion of appearance.The ratio contains rate, gold according to the liposome for containing the compatible metal ion of biology
The valence state for belonging to ion release rate in vivo and metal ion is calculated.For example, biology can be with high molecular material and containing metal
The volume ratio of cationic lipid liquid solution is 1:0.1~10, wherein liposome particles size is 0.3~500 μm, the packet of metal ion
Load rate is 10~80%, and the release rate of metal ion is 80~90%.
3, mixed liquor is hatched, obtains hydrogel.
The temperature of the hatching be 30~60 DEG C, the reaction time, that is, gel time be 0.1~for 24 hours.The hydrogel
To be chemically crosslinked state.
The hatching is to be reacted in 30~60 DEG C of climatic chamber.Further, the temperature of the hatching is
Body temperature, as 36~38 DEG C.
The preparation flow schematic diagram of the hydrogel of the active aldehyde radical of the present invention and bio-ligand is as shown in Fig. 2, natural high
Molecular material 400 is oxidized the high molecular material 500 for generating active aldehyde radical, then graft reaction occurs with bio-ligand 600,
Generate the high molecular material 200 of active aldehyde radical and bio-ligand.The high molecular material of active aldehyde radical and bio-ligand
200 mix with natural macromolecular material 400, the liposome 100 for containing the compatible metal ion of biology at 20 DEG C, are mixed
Liquid 700, the release metal ions at 37 DEG C of mixed liquor 700 form the hydrogel 300 of cross-linked structure.
Hydrogel prepared by the present invention has the characteristics that：(1) there is good syringeability, minimally invasive hand can be passed through
Art is injected into human body；(2) body temperature generation internal chemical can be perceived to be crosslinked and gelation, mechanical strength with higher；(3) have
Good self-repairability can avoid performing the operation again, may advantageously facilitate blood vessel even if self-healing can also be realized in vivo by being destroyed
Change, there is longer service life, and various bioactivators can be loaded；(4) there is good biological compatibility, life
Object degradability.
Invention further provides above-mentioned hydrogels as application biomedical, in tissue engineering material.Especially
It is the application in the transmitting of the repair materials in medical tissue, organizational project cell carrier and the factor or drug.
Embodiment
It is special below to lift preferred embodiment to allow the present invention to be clearer and more comprehensible, it elaborates, protection scope of the present invention is not
It is limited by the following examples.It is all within marrow and principle of the invention, any modification, equivalent replacement, improvement and so on,
It should all be included in the protection scope of the present invention.
Embodiment 1
(1) preparation of the liposome of the compatible metal ion of biology is contained
10mL chloroform is measured, the liposome solutions that configuration concentration is 2%, wherein the mass ratio of DPPC and DMPC is 9:
1；Then solution vacuum rotary steam, revolving temperature are 50 DEG C, revolving speed 60rpm.A transparent liposome membrane is finally obtained, to
With.Configuration concentration is that the calcium chloride solution of 0.4mol/L mixes liposome membrane with calcium chloride solution at a temperature of 55 DEG C,
And with probe type ultrasonic generator be ultrasonically treated 30min after, power 100w；Then mixed solution is cooled to room temperature, is used
4000g centrifugal force is centrifuged, and absolute alcohol is added in obtained sediment, and solution is made to form the suspension solution of 4mol/L ethyl alcohol；
Suspension is heated to 50 DEG C, dry nitrogen is then blasted, is completely removed to alcohol；Finally under ice bath, with etc. infiltrations it is slow
It rushes salt water to wash concentrate, and the eccentric cleaning under the centrifugal force of 5000g, be repeated 3 times.Permeate normal saline buffer solution
Preparation method is to prepare 0.9% sodium chloride solution 1L, and 10mmol/L HEPES and 1mmol/L EDTA is then added, to completely molten
Solution, with 5mol/L sodium hydrate regulator solution pH value, makes its pH value 7.4.The partial size for finally obtaining calcium ions liposome is big
Small is 0.1~100 μm.
(2) preparation of hydrogel
The alginate aqueous solution that configuration concentration is 5%, the molecular weight of alginate are 3 × 105Da, it is spare；Then plus
Entering to contain calcium ion liposome powder, the concentration of calcium ion is 0.1mol/L, it is uniformly mixed to solution, hatches at 37 DEG C,
Alginic acid hydrogel is obtained after 30min.
Embodiment 2
(1) it is as described in Example 1 to contain preparing for metal ion liposome.
(2) preparation of the high molecular material of active aldehyde radical
The collagen solution for being 5mg/mL with the acetic acid configuration concentration of 0.1wt%, collagen are after being freeze-dried
Collagen solids.Then sodium metaperiodate is added to aoxidize it, the additional amount of sodium metaperiodate is that mole is added in collagen
1.5 times, oxidation time 1h, ethylene glycol is then added and terminates reaction, the amount and sodium metaperiodate additional amount that ethylene glycol is added
Molar ratio be 1:1, it is then dialysed with the bag filter that molecular cut off is 8000Da, changes water three times daily, dialysed three days；
Finally in -80 DEG C of freezing 2h, then it is freeze-dried 72h, obtains the collagen compound of active aldehyde radical.
(3) preparation of hydrogel
With the collagen compound of the active aldehyde radical of the acetate dissolution of 0.1wt%, being configured to concentration is 5mg/mL's
The collagen solution of active aldehyde radical is configured with the HEPES of 50mmol/L, 0.75mol/L NaCl and 0.75mol/L KCl
HEPES buffer solution, it is spare；It is 2 that collagen solution and HEPES, which are buffered according to volume ratio,:1 mixing, then use 0.28mol/L
NaOH adjust pH 7.4, prepare the presoma of collagen gel；The liposome powder and glue of metal ion will finally be contained
The presoma of former protein gel mixes, and volume ratio is according to 1:2 mixing, hatch at 37 DEG C, obtain active aldehyde radical after 4~8h
Collagen hydrogels.
Embodiment 3
(1) the preparation such as embodiment 1 of the liposome of the compatible metal ion of biology is contained
It is shown.
(2) preparation of hydrogel
The alginate aqueous solution that configuration concentration is 3%, the molecular weight of alginate are 3 × 105Da, it is spare；Then plus
Enter to contain calcium ion liposome powder, the concentration of calcium ion is 0.1mol/L, obtains mixed solution A, spare；With 0.5mol/L's
The concentration that acetum dissolves mussel attachment proteins McfP-3, McfP-3 is 3mg/mL, obtains mixed solution B, by solution A and molten
Liquid B is 3 according to volume ratio:1 mixing, it is to be mixed complete, hatch at 37 DEG C, the seaweed with bio-ligand is obtained after 30min
Acid hydrogel.
Embodiment 4
(1) it is as described in Example 1 to contain preparing for the liposome of the compatible metal ion of biology.
(2) preparation of hydrogel
The alginate aqueous solution that configuration concentration is 3%, the molecular weight of alginate are 3 × 105Da, it is spare；Then plus
Enter to contain calcium ion liposome powder, the concentration of calcium ion is 0.1mol/L, obtains mixed solution A, spare；With water configuration concentration
For 5% hyaluronate solution C, wherein the molecular weight of hyaluronic acid is 1 × 106Da；Mussel is dissolved with 5% acetum
The concentration of attachment proteins McfP-4, McfP-4 are 4mg/ml, mixed solution E are obtained, by solution A, solution C and solution E according to body
Product is than being 3:1:1 mixing, it is to be mixed to hatch at 37 DEG C completely, the alginic acid with bio-ligand/transparent is obtained after 30min
Matter acid hydrogel.
Embodiment 5
(1) it is as described in Example 1 to contain preparing for the liposome of the compatible metal ion of biology, it will be therein
0.4mol/L calcium chloride solution is changed to 0.8mol/L ferric chloride solution；
(2) preparation of the high molecular material of active aldehyde radical
Then the hyaluronate solution for being 3% with water configuration concentration is added sodium metaperiodate and aoxidizes to it, periodic acid
The additional amount of sodium is mole is added in hyaluronic acid 1.3 times, oxidation time 0.5h, and ethylene glycol is then added and terminates instead
It answers, the molar ratio of amount and sodium metaperiodate additional amount that ethylene glycol is added is 1:1, the dialysis for being then 8000Da with molecular cut off
Bag is dialysed, and changes water three times daily, is dialysed three days；Finally in -80 DEG C of freezing 2h, then it is freeze-dried 72h, obtained active
The hyaluronic acid compound of aldehyde radical.
(3) preparation of active aldehyde radical and bio-ligand high molecular material
The hyaluronic acid compound for weighing the active aldehyde radical of 0.2g, is dissolved in 8mL water, wait be completely dissolved；So
0.2g EDC and 0.2g NHS is added afterwards, dissolves it sufficiently, adjusts its pH with 0.1mol/L sodium hydroxide, make its pH value
5.5, then it is passed through nitrogen 30min, the oxygen in solution is removed, DOPA is then added, mole of DOPA and hyaluronic acid aldehyde is added
Than being 1:2, it is protected from light for 24 hours, the solution after reaction is dialysed with the bag filter that molecular cut off is 3500Da, is changed daily
Water three times is dialysed three days；Finally in -80 DEG C of freezing 2h, then be freeze-dried 72h, obtain the active aldehyde radical of white sponge and
The hyaluronic acid compound of bio-ligand.
(4) preparation of hydrogel
It is the hyaluronic acid compound solution of 5% active aldehyde radical and bio-ligand with water compound concentration；Then it is added
Ferric ion liposome powder is contained, the concentration of iron ion is 0.15mol/L, then hatches at 37 DEG C, obtains after 30min
The hyaluronic acid gel of active aldehyde radical and bio-ligand.
Embodiment 6
(1) it is as described in Example 1 to contain preparing for the liposome of the compatible metal ion of biology.
(2) high molecular material of active aldehyde radical prepare it is as described in Example 5.
(3) active aldehyde radical and bio-ligand high molecular material prepare it is as described in Example 5.
(4) preparation of hydrogel.
The solution that concentration is 6% is obtained with the hyaluronic acid compound that water dissolves active aldehyde radical and bio-ligand；With
The alginate solution that water configuration concentration is 8% is 2 according to volume ratio:1 mixing, obtains mixed solution I, is then added and contains
The concentration of the liposome solutions of calcium ion, calcium ion is 0.18mol/L, finally hatches at 37 DEG C, seaweed is obtained after 30min
The hyaluronic acid gel of acid/active aldehyde radical and bio-ligand.
Embodiment 7
(1) it is as described in Example 5 to contain preparing for the liposome of the compatible metal ion of biology.
(2) high molecular material of active aldehyde radical prepare it is as described in Example 5.
(3) active aldehyde radical and bio-ligand high molecular material prepare it is as described in Example 5.
(4) preparation of hydrogel.
The solution that concentration is 6% is obtained with the hyaluronic acid compound that water dissolves active aldehyde radical and bio-ligand；With
The Chitosan salt solutions that acetic acid configuration concentration is 3%, are 1 according to volume:1 mixing, obtains mixed solution F, is then added and contains
Have a liposome solutions of calcium ion, the concentration of calcium ion is 0.2mol/L, is finally hatched at 37 DEG C, obtained after 6h chitosan/
The hyaluronic acid gel of active aldehyde radical and bio-ligand.
Embodiment 8
(1) it is as described in Example 1 to contain preparing for the liposome of the compatible metal ion of biology.
(2) high molecular material of active aldehyde radical prepare it is as described in Example 5.
(3) have preparing for bio-ligand high molecular material as described in Example 5.
(4) preparation of hydrogel.
The solution that concentration is 6% is obtained with the hyaluronic acid compound that water dissolves active aldehyde radical；With water configuration concentration
It is 2 according to volume ratio for 8% alginate solution:1 mixing, obtains mixed solution J, the rouge containing calcium ion is then added
Plastid solution, the concentration of calcium ion are 0.18mol/L, are finally hatched at 37 DEG C, and alginic acid/active is obtained after 30min
The hyaluronic acid gel of aldehyde radical.
Claims (8)
1. a kind of hydrogel comprising biology can with high molecular material, contain the compatible metal ion of biology liposome and
Water, the liposome can be cross-linked with each other with the biology with high molecular material, and the biology can use the volume hundred of high molecular material
Score is 10~49%, and the percentage by volume of the liposome for containing the compatible metal ion of biology is 5~49%, described
The percentage by volume of water is 2~85%, and the biology can include natural macromolecular material, active aldehyde radical with high molecular material
High molecular material, the high molecular material with bio-ligand and active aldehyde radical and bio-ligand high molecular material in
Two or more, the natural macromolecular material include alginic acid, hyaluronic acid, chondroitin sulfate, collagen, chitosan,
One of gelatin, fibroin albumen, keratoprotein, starch, polypeptide and its salt are a variety of, and the bio-ligand includes hydrochloric acid DOPA
One or both of amine and mussel attachment proteins, the compatible metal ion of biology includes Na+、K+、Ca2+、Fe3+、Zn2+With
Mn3+One or more of.
2. hydrogel as described in claim 1, which is characterized in that the mussel attachment proteins include Perna viridis byssus egg
White, Trachyostracous mussel byssus protein 1, Trachyostracous mussel byssus protein 2, Trachyostracous mussel byssus protein 3, Trachyostracous mussel byssus protein 4, thickness
One or more of shell mussel byssus protein 5 and Trachyostracous mussel byssus protein 6.
3. a kind of preparation method of hydrogel as described in claim 1, includes the following steps：
Preparation contains the liposome of the compatible metal ion of biology；
Into the solution that can use high molecular material containing biology, the liposome for containing the compatible metal ion of biology is added and mixes
It closes uniformly, obtains mixed liquor, the biology can include the high score of natural macromolecular material, active aldehyde radical with high molecular material
Two kinds in the high molecular material of sub- material, the high molecular material with bio-ligand and active aldehyde radical and bio-ligand or
Two or more, the natural macromolecular material includes alginic acid, hyaluronic acid, chondroitin sulfate, collagen, chitosan, gelatin, silk
One of fibroin, keratoprotein, starch, polypeptide and its salt are a variety of, and the bio-ligand includes Dopamine hydrochloride and makes a gift of
One or both of shellfish attachment proteins, the compatible metal ion of biology includes Na+、K+、Ca2+、Fe3+、Zn2+And Mn3+In
One or more；
Mixed liquor is hatched, hydrogel is obtained.
4. preparation method as claimed in claim 3, which is characterized in that the high molecular material of the active aldehyde radical is by such as
Lower step is made：Natural macromolecular material is dissolved in solvent, oxidant is added and carries out oxidation reaction, it is high to obtain active aldehyde radical
Molecular material.
5. preparation method as claimed in claim 4, which is characterized in that the oxidant includes potassium chlorate, chromium trioxide, dioxygen
One or more of water and sodium metaperiodate.
6. preparation method as claimed in claim 5, which is characterized in that the high molecular material with bio-ligand has
The high molecular material of active aldehyde radical and bio-ligand is made as follows：By natural macromolecular material or active aldehyde radical
High molecular material be dissolved in solvent, adjust pH value, be passed through nitrogen, add bio-ligand, be protected from light, obtain have biology
The high molecular material of the high molecular material of ligand or active aldehyde radical and bio-ligand.
7. preparation method as claimed in claim 3, which is characterized in that into the solvent that can use high molecular material containing biology,
It is added the liposome for containing the compatible metal ion of biology by preset ratio, the ratio is according to containing biological compatible gold
Belong to the liposome of ion contain rate, metal ion release rate in vivo and the valence state of metal ion is calculated.
8. a kind of hydrogel as described in claim 1 is as the application in biological organization material.
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| CN107158453B (en) * | 2017-06-02 | 2020-02-18 | 武汉纺织大学 | Preparation method of hyaluronic acid tissue adhesive |
| CN109666178A (en) * | 2017-10-17 | 2019-04-23 | 翁秋梅 | A kind of hydridization dynamic aggregation compositions and its application |
| CN108192427B (en) * | 2018-01-12 | 2019-12-24 | 吉林大学 | Dopamine-hyaluronic acid coating material, preparation method and application of dopamine-hyaluronic acid coating material in aspect of promoting specific adhesion of dental pulp stem cells to dentin |
| CN108478485A (en) * | 2018-05-04 | 2018-09-04 | 邵立坤 | A kind of temperature-sensitive hydrogel facial mask and preparation method thereof |
| CN111387508A (en) * | 2020-03-12 | 2020-07-10 | 大连工业大学 | Zinc chelating peptide gel and preparation method thereof |
| CN112370437B (en) * | 2020-10-20 | 2022-10-21 | 好医生药业集团有限公司 | Amoxicillin capsule and preparation method thereof |
| CN112316204B (en) * | 2020-11-13 | 2021-08-27 | 四川大学 | Metal polyphenol collagen membrane material, preparation method and application thereof |
| CN114272206B (en) * | 2021-02-08 | 2023-06-09 | 四川大学 | Injectable antibacterial polymer hydrogel and preparation method and application thereof |
| CN112957521B (en) * | 2021-04-01 | 2022-06-10 | 浙江理工大学 | Preparation method of alginate-silk fibroin composite hydrogel carrying artemisinin liposome |
| CN113877000B (en) * | 2021-10-13 | 2023-01-24 | 科笛生物医药(无锡)有限公司 | Microsphere composition for injection and application thereof |
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