CN105597156A - Hydrogel as well as preparation method and application thereof - Google Patents
Hydrogel as well as preparation method and application thereof Download PDFInfo
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- CN105597156A CN105597156A CN201510986012.0A CN201510986012A CN105597156A CN 105597156 A CN105597156 A CN 105597156A CN 201510986012 A CN201510986012 A CN 201510986012A CN 105597156 A CN105597156 A CN 105597156A
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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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- 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
- A61L27/02—Inorganic materials
- A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
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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
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
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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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
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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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
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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
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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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
- A61L27/58—Materials at least partially resorbable by the body
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
Abstract
Hydrogel comprises a liposome entrapping bio-compatible metal ions, a bio-available high polymer material and water, wherein the liposome and the bio-available high polymer material are cross-linked with each other, the bio-available high polymer material accounts for 10%-49% by volume, the liposome entrapping the bio-compatible metal ions accounts for 5%-49% by volume, and the water accounts for 2%-85% by volume. The invention further provides a preparation method and an application of the hydrogel. The bio-compatible metal ions entrapped in the hydrogel can restrain the gel formation and performance regulation of the liposome. The hydrogel releases the metal ions specifically at the body temperature of 37 DEG C to promote high polymer crosslinking to form a network structure after the hydrogel is injected into a human body, that is, the hydrogel can be gelled rapidly by sensing the temperature change in the body and has a better temperature sensitive characteristic.
Description
Technical field
The present invention relates to biomedical materials field, particularly relate to a kind of hydrogel and its preparation method and application.
Background technology
Hydrogel has tridimensional network and certain mechanical property, for the conveying of cytotrophy material, oxygen and metabolite and exchange provide good transport channel, simultaneously for cell is built three dimensional growth environment, part hydrogel still has the biophysics characteristics such as the new vessels of promotion formation, therefore hydrogel has certain advantage aspect cell carrier, for example, can be used as the material of plastotype support.
Tradition hydrogel support is mostly external plastotype in advance, then be implanted to precalculated position in body by the mode of operation, but due to human body defective tissue or very irregularity of the common shape of organ, the shape of timbering material often cannot fit like a glove with target site, and is difficult to avoid cause in surgical procedure the secondary insult to patient.
Summary of the invention
In view of this, the invention provides a kind of hydrogel that can gelation after being injected in vivo.
A kind of hydrogel, it comprises that biological available macromolecular material, bag carry liposome and the water of biological compatible metal ion, described liposome and the available macromolecular material of described biology are cross-linked with each other, wherein the percentage by volume of biological available macromolecular material is 10 ~ 49%, the percentage by volume that described bag carries the liposome of biological compatible metal ion is 5 ~ 49%, and the percentage by volume of described water is 2 ~ 85%.
Further, biological available macromolecular material comprise natural macromolecular material, have active aldehyde radical macromolecular material, there is the macromolecular material of bio-ligand and there are one or more in the macromolecular material of active aldehyde radical and bio-ligand.
A preparation method for above-mentioned hydrogel, comprises the steps:
Preparation bag carries the liposome of biological compatible metal ion;
In the solvent that contains biological available macromolecular material, add bag carry the liposome of biological compatible metal ion and mix, obtain mixed liquor;
By mixed liquor temperature reaction, obtain hydrogel.
A kind of hydrogel is in the application as in biological organization material.
The biology that in hydrogel of the present invention, bag carries can compatible metal ion, can fetter liposome and regulate formation and the performance of gel. This hydrogel can be injected into after human body, and at 37 DEG C of body temperature, specific release metal ions inspires macromolecule and is cross-linked to form network structure, can the gelation rapidly by variations in temperature in perception body, there is good temperature-sensing property. Therefore, hydrogel of the present invention can adopt Minimally Invasive Surgery to be injected directly into demand position, according to the variation of temperature original position plastic in vivo, adapt to the moulding of individuation shape, overcome the problems such as the shape of the outer preformed of traditional water gel, timbering material and target site can not fit like a glove, avoided patient's secondary insult.
Brief description of the drawings
Fig. 1 has the hydrogel Thermo-sensitive dynamics schematic diagram of active aldehyde radical and bio-ligand.
Fig. 2 has the preparation flow schematic diagram of the hydrogel of active aldehyde radical and bio-ligand.
Main element symbol description
| Bag carries the liposome of biological compatible metal ion | 100 |
| There is the macromolecular material of active aldehyde radical and bio-ligand | 200 |
| There is the hydrogel of active aldehyde radical and bio-ligand | 300 |
| Natural macromolecular material | 400 |
| There is the macromolecular material of active aldehyde radical | 500 |
| Bio-ligand | 600 |
| Mixed liquor | 700 |
Following detailed description of the invention further illustrates the present invention in connection with above-mentioned accompanying drawing.
Detailed description of the invention
A kind of hydrogel of the present invention's protection; it comprises that biological available macromolecular material, bag carry liposome and the water of biological compatible metal ion; described liposome and the available macromolecular material of described biology are cross-linked with each other; the percentage by volume of the available macromolecular material of described biology is 10 ~ 49%; wherein the percentage by volume of the liposome of bag year biological compatible metal ion is 5 ~ 49%, and the percentage by volume of described water is 2 ~ 85%.
The liposome that above-mentioned bag carries in the liposome of biological compatible metal ion includes but not limited to dipalmitoyl-phosphate ester phatidylcholine (Dipalmitoylphosphatidylcholine; DPPC), dimyristoyl phosphatidyl choline (1; 2-Dimyristoyl-sn-glycero-3-phosphocholine; DMPC), two myristoyl trimethyl ammonium propane (1; 2-dimyristoyl-3-trimethylammoniumpropane; DMTAP) one or more and in DSPC (DistearoylPhosphatidylcholine, DSPC).
Described biology can compatible metal ion be that organism can absorb the metal ion that can't work the mischief. Include but not limited to and good 1 valency of human-body biological compatibility, divalent or 3 valence metal ions, especially sodium ion (Na+), potassium ion (K+), calcium ion (Ca2+), iron ion (Fe3+), zinc ion (Zn2+) and manganese ion (Mn3+) in one or more.
Hydrogel of the prior art is more to be solidified in vitro or forms cross-linked structure, can only be implanted in body by external plasticity again. The biology that hydrogel bag of the present invention carries can compatible metal ion can fetter liposome and regulate formation and the performance of gel. This hydrogel can be injected into after human body, and at 37 DEG C of body temperature, specific release metal ions inspires macromolecule and is cross-linked to form network structure, can the gelation rapidly by variations in temperature in perception body, there is good temperature sensitivity, i.e. Thermo-sensitive. Therefore, hydrogel of the present invention can adopt Minimally Invasive Surgery to be injected directly into demand position, according to the variation of temperature original position plastic in vivo, adapt to the moulding of individuation shape, overcome the problems such as the shape of the outer preformed of traditional water gel, timbering material and target site can not fit like a glove, avoided patient's secondary insult.
Further, the available macromolecular material of described biology comprise natural macromolecular material, have active aldehyde radical macromolecular material, there is the macromolecular material of bio-ligand and there are one or more in the macromolecular material of active aldehyde radical and bio-ligand.
Above-mentioned bio-ligand includes but not limited to one or more of Dopamine hydrochloride and mussel attachment proteins, especially Dopamine hydrochloride (DopamineHydrochloride, DOPA), Perna viridis byssus albumen (Pernaviridisfootprotein, Pvfp) one or more and in mussel attachment proteins (musseladhesiveprotein, MAP). Wherein MAP includes but not limited to Trachyostracous mussel byssus albumen 1(Mytiluscoruscusfootprotein1, McfP1), Trachyostracous mussel byssus albumen 2(McfP2), Trachyostracous mussel byssus albumen 3(McfP3), Trachyostracous mussel byssus albumen 4(McfP4), Trachyostracous mussel byssus albumen 5(McfP5) and Trachyostracous mussel byssus albumen 6(McfP6) in one or more. Be preferably one or more in McfP3, McfP4, McfP5. Described bio-ligand all contains more Dopamine hydrochloride (DOPA) and hydroxyproline (hydroxyproline, Hyp), can with biological tissue in protein isopolarity polymer form very strong hydrogen bond, there is stronger adhesion activity.
Above-mentioned natural macromolecular material includes but not limited to one or more of polysaccharide, protein and its salt. Especially one or more in alginic acid, hyaluronic acid, chondroitin sulfate, collagen, shitosan, gelatin, fibroin albumen, keratoprotein, starch, polypeptide and its salt. Described polysaccharide, protein and its salt all have good human-body biological compatibility.
Therefore in the present invention, there is the hydrogel of the Polymer materialspreparation of bio-ligand, there is superpower adhesion property, the bio-ligand containing in hydrogel and the liposome generation chelation that wraps year biological compatible metal ion, carry out chemical crosslinking, form the structure of interpenetrating networks, further strengthen stability and the adhesiveness of hydrogel, realized the chemical dynamics self-repair function under hygrometric state, and then extend hydrogel service life in vivo, improve cell delay and activity in vivo.
In addition, in the present invention, have aldehyde radical in the hydrogel of Polymer materialspreparation of active aldehyde radical can with histone in amino and other natural macromolecular materials in amino generation schiff base reaction form the hydrogel of covalent cross-linking, improved mechanical property and the cellular affinity of hydrogel.
Further, the hydrogel in the present invention with the Polymer materialspreparation of active aldehyde radical and bio-ligand possesses syringeability simultaneously, the feature of Thermo-sensitive and self-healing property, it is the temperature sensitive self-healing property multifunctional water of a kind of new injectable gel, its Thermo-sensitive dynamics schematic diagram as shown in Figure 1, biological can compatible metal ion and liposome generate in vitro bag and carry the liposome 100 of biological compatible metal ion, it generates the hydrogel 300 with active aldehyde radical and bio-ligand with the macromolecular material 200 with active aldehyde radical and bio-ligand again, this hydrogel in vivo at 37 DEG C specific release metal ions inspire macromolecule and be cross-linked to form network structure. the principle of this hydrogel mimic biology body wound healing, once material produces defect, without external influence in the situation that, realizes the self-healing of micro-crack. this function can extend material service life in vivo.
Further, the hydrogel in the present invention, all adopts the natural material preparation with good biological compatibility, and it has excellent biological compatibility, degradation property, special cytosis site.
The preparation method who the present invention further provides above-mentioned hydrogel, comprises the steps:
1, preparation bag carries the liposome of biological compatible metal ion;
In above-mentioned preparation method, the liposome that described preparation bag carries biological compatible metal ion is made as follows: liposome compound is dissolved in to organic solvent, add the aqueous solution that contains biological compatible metal ion, mix, obtain the liposome of bag year biological compatible metal ion.
Described organic solvent includes but not limited to one or more in carrene and chloroform.
The concentration that described liposome compound is dissolved in after organic solvent is 1 ~ 500mg/mL, 1 ~ 400mg/mL, 1 ~ 300mg/mL, 1 ~ 200mg/mL, 1 ~ 100mg/mL or 1 ~ 50mg/mL.
Further, also the organic solution of liposome compound can be made to dry thing, its method can adopt the conventional method of any those skilled in the art, for example, and intensification, vacuum drying etc. The present invention preferably adopts the method for revolving steaming, and liposome compound organic solution is made to liposome membrane. Revolving and steaming temperature is 20 ~ 70 DEG C, and rotating speed is 50 ~ 200rpm.
The concentration of the aqueous solution of the compatible metal ion of described 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, for promoting that liposome fully reacts with metal ion, in reaction, can be warming up to uniform temperature, this temperature is preferably 40 ~ 80 DEG C. Further, reaction system can also be placed in to ultrasonic generator ultrasonic, 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, and ultrasonic power is 50 ~ 200w.
If have intensification when reaction, question response finishes, and mixed solution can be cooled to room temperature.
It will be appreciated by those skilled in the art that, after reacting completely, further can also comprise purifying, dry. The method of purifying, can adopt the conventional method of any those skilled in the art, for example, filters, and washing, centrifugal etc. The present invention preferably adopts the unnecessary metal ion of centrifugal removal, and centrifugal force is 1000 ~ 30000g. Sediment is dissolved in alcohol organic solvent again, is preferably ethanol, concentration is 2 ~ 8mol/L, obtains white suspension. White suspension is passed into nitrogen, remove alcohol organic solvent. Finally, with waiting washing of infiltration physiological saline, centrifugal, this step is repeatedly capable of circulation. The infiltration physiological saline formula such as described is: 10mol/L4-HEPES (4-(2-hydroxyerhyl) piperazine-1-erhaesulfonicacid, HEPES), 1mmol/L disodium ethylene diamine tetraacetate (Ethylenediaminetetraaceticaciddisodiumsalt, EDTA), concentration is 0.9% sodium chloride, pH value 7.4.
The method of the dry liposome that makes bag year biological compatible metal ion is preferably freeze drying.
2, in the solvent that contains biological available macromolecular material, add bag carry the liposome of biological compatible metal ion and mix, obtain mixed liquor;
The available macromolecular material of described biology comprises natural macromolecular material, have the macromolecular material of active aldehyde radical, have the macromolecular material of bio-ligand and have one or more in the macromolecular material of active aldehyde radical and bio-ligand.
Described natural macromolecular material includes but not limited to one or more in alginic acid, hyaluronic acid, chondroitin sulfate, collagen, shitosan, gelatin, fibroin albumen, keratoprotein, starch, polypeptide and its salt.
The macromolecular material further, with active aldehyde radical is made as follows: natural macromolecular material is dissolved in to solvent, adds oxidant to carry out oxidation reaction, obtain having active aldehydes based high molecular material. Further, natural macromolecular material oxidation can be selected to oxidant well-known to those skilled in the art, such as potassium chlorate, chromium trioxide, hydrogen peroxide, sodium metaperiodate etc., be preferably sodium metaperiodate.
In specific embodiment, different natural macromolecular materials should be dissolved in different solvents. For example dissolve shitosan, fibroin albumen, keratoprotein, collagen, polypeptide etc. with organic acid. Water dissolves hyaluronic acid or its salt, alginic acid or its salt, starch, chondroitin sulfate or its salt etc. Described organic acid is preferably acetic acid or malonic acid.
Further, to reacting a period of time, also can add a certain amount of ethylene glycol cessation reaction. It will be appreciated by those skilled in the art that, after reaction finishes, can adopt the conventional method of any those skilled in the art by product separation and purification, remove impurity, for example, adopt the bag filter dialysis of certain molecular weight, also can adopt chromatographic isolation or milipore filter etc. The molecular weight of preferred bag filter used is 3000 ~ 8000Da.
Further, after separation and purification, can also be dried, preferably freeze drying, makes the macromolecular material with active aldehyde radical. Described freeze drying is freezing 2h under subzero 40 ~ 90 DEG C of ultralow temperature, puts into freeze drier, freeze drying 24h under subzero 50 ~ 60 DEG C of conditions after freezing.
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%, and molecular weight is 1.0 × 104~1.5×106Da. The above-mentioned amount that adds oxidant is 0.1 ~ 10 times that natural macromolecular material adds mole, and the reaction time is 0.5 ~ 12h. The mole that adds ethylene glycol is 1 ~ 5 times of sodium metaperiodate mole.
Further, the described macromolecular material that has the macromolecular material of bio-ligand or have active aldehyde radical and a bio-ligand is made as follows: natural macromolecular material or the macromolecular material with active aldehyde radical are dissolved in solvent, regulate pH, pass into nitrogen, add again bio-ligand, lucifuge reaction, the macromolecular material that obtains thering is the macromolecular material of bio-ligand or there is active aldehyde radical and bio-ligand.
The above-mentioned different macromolecular material with active aldehyde radical should be dissolved in different solvents. For example dissolve the shitosan, fibroin albumen, keratoprotein, collagen, polypeptide etc. with active aldehyde radical with organic acid; Water dissolves hyaluronic acid or its salt, alginic acid or its salt, chondroitin sulfate or its salt, the starch etc. with active aldehyde radical. Described organic acid is preferably acetic acid or malonic acid. The method that different natural macromolecular materials is dissolved in solvent as previously mentioned.
Further, also can add carboxyl activator, as carbodiimides (Carbodiimide, and N-hydroxy benzo triazole (NHydroxybenzotrizole EDC), HOBt) one or more, the macromolecular material that increases natural macromolecular material or have an active aldehyde radical reacts incidence with bio-ligand. Further can also add N-maloyl imines (N-Hydroxysuccinimide is called for short NHS) to reduce side reaction occurs.
It will be appreciated by those skilled in the art that the method that regulates the method for pH can use those skilled in the art conventionally to adopt for example regulates with certain density NaOH or hydrochloric acid.
It will be appreciated by those skilled in the art that, after reaction finishes, also can adopt the conventional method separation and purification of any those skilled in the art, remove impurity, for example, adopt the bag filter dialysis of certain molecular weight, also can adopt chromatographic isolation or milipore filter etc. The molecular weight of preferred bag filter used is 3000 ~ 8000Da.
Further, after separation and purification, can also be dried, preferably freeze drying, makes the macromolecular material with bio-ligand. Described freeze drying is freezing 2h under subzero 40 ~ 90 DEG C of ultralow temperature, puts into freeze drier, freeze drying 24h under subzero 50 ~ 60 DEG C of conditions after freezing.
Further, described bio-ligand is one or more in Dopamine hydrochloride, Perna viridis keratoprotein and mussel attachment proteins. Further, described mussel attachment proteins is one or more in McfP1, McfP2, McfP3, McfP4, McfP5 and McfP6. Be preferably one or more in McfP3, McfP4, McfP5.
In the time that natural macromolecular material or the concentration with the solution of the macromolecular material of active aldehyde radical are 0.2 ~ 1wt%, the amount of dehydrating agent is natural macromolecular material or the macromolecular material with active aldehyde radical 2 times, if the addition of EDC is 2 times of polymer mole, and being EDC, the addition of NHS adds 2 times of mole. The above-mentioned pH adjusting agent adding as the concentration of NaOH be the concentration 0.5-2mol/L of 1 ~ 5mol/L or hydrochloric acid, pH value is 3 ~ 6.
The amount of the described bio-ligand adding is according to the molecular weight of bio-ligand and different. The addition of for example DOPA is natural macromolecular material or the macromolecular material mole with active aldehyde radical 0.1 ~ 10 times; The addition of Pvfp is natural macromolecular material or the mole with the macromolecular material of active aldehyde radical 0.1 ~ 5 times; The addition of McfP-3, McfP-4, McfP-5 is natural macromolecular material or the macromolecular material mole with active aldehyde radical 0.1 ~ 8 times. The time of lucifuge reaction is 1 ~ 24h.
It will be appreciated by those skilled in the art that, natural macromolecular material or there is the macromolecular material of active aldehyde radical and bio-ligand mixes, and the sequencing mixing with bag carrying metal ion liposome does not limit. For example, in specific embodiment, can be first natural macromolecular material or macromolecular material and the bio-ligand with active aldehyde radical be mixed, then the liposome that carries biological compatible metal ion with bag mixes. Also can be first by natural macromolecular material or there is the macromolecular material of active aldehyde radical and liposome that bag carries biological compatible metal ion mixes, then mix with bio-ligand. Also can be first by part natural macromolecular material or there is the macromolecular material of active aldehyde radical and liposome that bag carries biological compatible metal ion mixes, then with remainder natural macromolecular material or have the macromolecular material of active aldehyde radical, bio-ligand mixes.
Further, the macromolecular material with bio-ligand is mixed with the liposome that bag carries biological compatible metal ion, can first the macromolecular material with bio-ligand be dissolved in to solvent. The different macromolecular materials with bio-ligand should be dissolved in different solvents, for example, dissolve the shitosan, fibroin albumen, keratoprotein, collagen, polypeptide etc. with bio-ligand with organic acid; Water dissolves hyaluronic acid or its salt, alginic acid or its salt, chondroitin sulfate or its salt, the starch etc. with bio-ligand. Described organic acid is preferably acetic acid or malonic acid. In like manner, natural macromolecular material and have active aldehyde radical macromolecular material solution configuration as previously mentioned.
Further, in the solvent that contains biological available macromolecular material, add bag to carry the liposome of biological compatible metal ion by preset ratio. The bag of liposome that described ratio is carried biological compatible metal ion according to bag carries release rate in vivo of rate, metal ion and the valence state of metal ion calculates. For example, the volume ratio of biological available macromolecular material and metal ion liposome solutions is 1:0.1 ~ 10, and wherein liposome particles size is 0.3 ~ 500 μ m, and the bag rate of carrying of metal ion is 10 ~ 80%, and the release rate of metal ion is 80 ~ 90%.
3, by mixed liquor hatching, obtain hydrogel.
The temperature of described hatching is 30 ~ 60 DEG C, and the described reaction time is that gel time is 0.1 ~ 24h. Described hydrogel is chemical crosslinking state.
Described hatching for to react in the climatic chamber of 30 ~ 60 DEG C. Further, the temperature of described hatching is body temperature, is 36 ~ 38 DEG C.
The present invention have active aldehyde radical and bio-ligand hydrogel preparation flow schematic diagram as shown in Figure 2, the oxidized generation of natural macromolecular material 400 has the macromolecular material 500 of active aldehyde radical, there is graft reaction with bio-ligand 600 again, generate the macromolecular material 200 with active aldehyde radical and bio-ligand. The macromolecular material 200 with active aldehyde radical and bio-ligand mixes at 20 DEG C with the liposome 100 that natural macromolecular material 400, bag carry biological compatible metal ion, obtain mixed liquor 700, mixed liquor 700 is release metal ions at 37 DEG C, forms the hydrogel 300 of cross-linked structure.
The prepared hydrogel of the present invention has following characteristics: (1) has good syringeability, can be expelled to human body by Minimally Invasive Surgery; (2) can perception body temperature there is inner chemical crosslinking and gelation has higher mechanical strength; (3) there is good self-repairability, also can realize self-healing even destroyed in vivo, can avoid again performing the operation, be conducive to promote vascularization, there is longer service life, and can load various bioactivators; (4) there is good biological compatibility, biological degradability.
The present invention further provides above-mentioned hydrogel in the application as in biomedicine, tissue engineering material. Especially the application in the transmission of repair materials, organizational project cell carrier and the factor or the medicine of medical tissue.
Embodiment
For allowing the present invention become apparent, below especially exemplified by preferred embodiment, elaborate, protection scope of the present invention is not limited by the following examples. All within marrow of the present invention and principle, any amendment of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Embodiment 1
(1) bag carries the preparation of the liposome of biological compatible metal ion
Measure 10mL chloroform, the liposome solutions that configuration concentration is 2%, wherein the mass ratio of DPPC and DMPC is 9:1; Then solution decompression revolves steaming, and revolving and steaming temperature is 50 DEG C, and rotating speed is 60rpm. Finally obtain a transparent liposome membrane, stand-by. Configuration concentration is the calcium chloride solution of 0.4mol/L, at 55 DEG C of temperature, liposome membrane is mixed with calcium chloride solution, and with after the ultrasonic processing of probe type ultrasonic generator 30min, power is 100w; Then mixed solution is cooled to room temperature, carries out centrifugally with 4000g centrifugal force, the sediment obtaining adds absolute alcohol, makes solution form the suspension solution of 4mol/L ethanol; Suspension is heated to 50 DEG C, then blasts dry nitrogen, treat that alcohol removes completely; Finally under ice bath, with etc. infiltration BS concentrate is washed, and under the centrifugal force of 5000g eccentric cleaning, repeat 3 times. Infiltration normal saline buffer solution preparation method, for preparation 0.9% sodium chloride solution 1L, then adds 10mmol/LHEPES and 1mmol/LEDTA, treats to dissolve completely, and by 5mol/L sodium hydrate regulator solution pH value, making its pH value is 7.4. The particle size that finally obtains calcium ions liposome is 0.1 ~ 100 μ m.
(2) preparation of hydrogel
Configuration concentration is 5% the alginate aqueous solution, and the molecular weight of alginate is 3 × 105Da, for subsequent use; Then add bag to carry calcium ion liposome powder, the concentration of calcium ion is 0.1mol/L, treats that solution mixes, and at 37 DEG C, hatching, obtains alginic acid hydrogel after 30min.
Embodiment 2
(1) preparation of bag carrying metal ion liposome as described in Example 1.
(2) there is the preparation of the macromolecular material of active aldehyde radical
The collagen solution that is 5mg/mL with the acetic acid configuration concentration of 0.1wt%, collagen is the collagen solid after freeze drying. Then add sodium metaperiodate to be oxidized it, the addition of sodium metaperiodate is 1.5 times that collagen adds mole, oxidation time is 1h, then add ethylene glycol cessation reaction, the mol ratio of the amount that ethylene glycol adds and sodium metaperiodate addition is 1:1, then dialyse with the bag filter that molecular cut off is 8000Da, change water every day three times, dialyse three days; Finally at-80 DEG C of freezing 2h, then freeze drying 72h, obtain having the collagen compound of active aldehyde radical.
(3) preparation of hydrogel
Have the collagen compound of active aldehyde radical with the acetate dissolution of 0.1wt%, being configured to concentration is the collagen solution with active aldehyde radical of 5mg/mL, with the HEPES of 50mmol/L, and 0.75mol/LNaCl and 0.75mol/LKCl configuration HEPES cushioning liquid, for subsequent use; Be that 2:1 mixes by collagen solution and HEPES buffering according to volume ratio, then with the NaOH adjusting pH7.4 of 0.28mol/L, prepare the presoma of collagen gel; Finally the liposome powder of bag carrying metal ion is mixed with the presoma of collagen gel, volume ratio is mixed according to 1:2,37 DEG C of hatchings, obtains having the collagen hydrogel of active aldehyde radical after 4 ~ 8h.
Embodiment 3
(1) preparation of the liposome of bag year biological compatible metal ion as described in Example 1.
(2) preparation of hydrogel
Configuration concentration is 3% the alginate aqueous solution, and the molecular weight of alginate is 3 × 105Da, for subsequent use; Then add bag to carry calcium ion liposome powder, the concentration of calcium ion is 0.1mol/L, obtains mixed solution A, for subsequent use; With the acetum dissolving mussel attachment proteins McfP-3 of 0.5mol/L, the concentration of McfP-3 is 3mg/mL, obtains mixed solution B, be that 3:1 mixes by solution A and solution B according to volume ratio, to be mixed complete, at 37 DEG C, hatch, after 30min, obtain having the alginic acid hydrogel of bio-ligand.
Embodiment 4
(1) preparation of the liposome of bag year biological compatible metal ion as described in Example 1.
(2) preparation of hydrogel
Configuration concentration is 3% the alginate aqueous solution, and the molecular weight of alginate is 3 × 105Da, for subsequent use; Then add bag to carry calcium ion liposome powder, the concentration of calcium ion is 0.1mol/L, obtains mixed solution A, for subsequent use; Water configuration concentration is 5% hyaluronate solution C, and wherein hyaluronic molecular weight is 1 × 106Da; Acetum with 5% dissolves mussel attachment proteins McfP-4, the concentration of McfP-4 is 4mg/ml, obtain mixed solution E, be that 3:1:1 mixes by solution A, solution C and solution E according to volume ratio, to be mixed complete, at 37 DEG C, hatch, after 30min, obtain having the alginic acid/hyaluronic acid gel of bio-ligand.
Embodiment 5
(1) preparation of the liposome of bag year biological compatible metal ion as described in Example 1, changes 0.4mol/L calcium chloride solution wherein into 0.8mol/L ferric chloride solution;
(2) there is the preparation of the macromolecular material of active aldehyde radical
Water configuration concentration is 3% hyaluronic acid salting liquid, then add sodium metaperiodate to be oxidized it, the addition of sodium metaperiodate is 1.3 times that hyaluronic acid adds mole, oxidation time is 0.5h, then add ethylene glycol cessation reaction, the mol ratio of the amount that ethylene glycol adds and sodium metaperiodate addition is 1:1, then dialyses with the bag filter that molecular cut off is 8000Da, change water every day three times, dialyse three days; Finally at-80 DEG C of freezing 2h, then freeze drying 72h, obtain having the hyaluronic acid compound of active aldehyde radical.
(3) there is the preparation of active aldehyde radical and bio-ligand macromolecular material
Weigh the hyaluronic acid compound that 0.2g has active aldehyde radical, be dissolved in 8mL water, treat to dissolve completely; Then add 0.2gEDC and 0.2gNHS, it is fully dissolved, regulate its pH with 0.1mol/L NaOH, making its pH value is 5.5, pass into again nitrogen 30min, remove the oxygen in solution, then add DOPA, the mol ratio that adds DOPA and hyaluronic acid aldehyde is 1:2, lucifuge reaction 24h, reacted solution is dialysed with the bag filter that molecular cut off is 3500Da, change water every day three times, dialyse three days; Finally at-80 DEG C of freezing 2h, then freeze drying 72h, obtain platinum sponge shape and have the hyaluronic acid compound of active aldehyde radical and bio-ligand.
(4) preparation of hydrogel
Water compound concentration is 5% to have the hyaluronic acid compound solution of active aldehyde radical and bio-ligand; Then add bag to carry ferric ion liposome powder, the concentration of iron ion is 0.15mol/L, then at 37 DEG C, hatches, and obtains having the hyaluronic acid gel of active aldehyde radical and bio-ligand after 30min.
Embodiment 6
(1) preparation of the liposome of bag year biological compatible metal ion as described in Example 1.
(2) have active aldehyde radical macromolecular material preparation as described in Example 5.
(3) preparation that has active aldehyde radical and a bio-ligand macromolecular material as described in Example 5.
(4) preparation of hydrogel.
Water dissolves the hyaluronic acid compound with active aldehyde radical and bio-ligand, and to obtain concentration be 6% solution; Water configuration concentration is 8% alginate solution, be that 2:1 mixes according to volume ratio, obtain mixed solution I, then add the liposome solutions that contains calcium ion, the concentration of calcium ion is 0.18mol/L, finally hatching at 37 DEG C, obtains alginic acid/the have hyaluronic acid gel of active aldehyde radical and bio-ligand after 30min.
Embodiment 7
(1) preparation of the liposome of bag year biological compatible metal ion as described in Example 5.
(2) have active aldehyde radical macromolecular material preparation as described in Example 5.
(3) preparation that has active aldehyde radical and a bio-ligand macromolecular material as described in Example 5.
(4) preparation of hydrogel.
Water dissolves the hyaluronic acid compound with active aldehyde radical and bio-ligand, and to obtain concentration be 6% solution; The chitosan salt solution that is 3% with acetic acid configuration concentration, mixed for 1:1 according to volume, obtain mixed solution F, then add the liposome solutions that contains calcium ion, the concentration of calcium ion is 0.2mol/L, finally hatching at 37 DEG C, obtains shitosan/the have hyaluronic acid gel of active aldehyde radical and bio-ligand after 6h.
Embodiment 8
(1) preparation of the liposome of bag year biological compatible metal ion as described in Example 1.
(2) have active aldehyde radical macromolecular material preparation as described in Example 5.
(3) preparation that has a bio-ligand macromolecular material as described in Example 5.
(4) preparation of hydrogel.
Water dissolves the hyaluronic acid compound with active aldehyde radical, and to obtain concentration be 6% solution; Water configuration concentration is 8% alginate solution, be that 2:1 mixes according to volume ratio, obtain mixed solution J, then add the liposome solutions that contains calcium ion, the concentration of calcium ion is 0.18mol/L, finally hatching at 37 DEG C, obtains alginic acid/the have hyaluronic acid gel of active aldehyde radical after 30min.
Claims (12)
1. a hydrogel, it comprises that biological available macromolecular material, bag carry liposome and the water of biological compatible metal ion, described liposome and the available macromolecular material of described biology are cross-linked with each other, the percentage by volume of the available macromolecular material of described biology is 10 ~ 49%, the percentage by volume that described bag carries the liposome of biological compatible metal ion is 5 ~ 49%, and the percentage by volume of described water is 2 ~ 85%.
2. hydrogel as claimed in claim 1, it is characterized in that, the available macromolecular material of described biology comprises natural macromolecular material, have the macromolecular material of active aldehyde radical, have the macromolecular material of bio-ligand and have one or more in the macromolecular material of active aldehyde radical and bio-ligand.
3. hydrogel as claimed in claim 2, it is characterized in that, described natural macromolecular material comprises one or more in alginic acid, hyaluronic acid, chondroitin sulfate, collagen, shitosan, gelatin, fibroin albumen, keratoprotein, starch, polypeptide and its salt.
4. hydrogel as claimed in claim 2, is characterized in that, described bio-ligand comprises one or more in Dopamine hydrochloride, Perna viridis byssus albumen and mussel attachment proteins.
5. hydrogel as claimed in claim 4, it is characterized in that, described mussel attachment proteins comprises one or more in Trachyostracous mussel byssus albumen 1, Trachyostracous mussel byssus albumen 2, Trachyostracous mussel byssus albumen 3, Trachyostracous mussel byssus albumen 4, Trachyostracous mussel byssus albumen 5 and Trachyostracous mussel byssus albumen 6.
6. hydrogel as claimed in claim 1, is characterized in that, described biology can comprise Na by compatible metal ion+、K+、Ca2+、Fe3+、Zn2+And Mn3+In one or more.
7. a preparation method for hydrogel as claimed in claim 1, comprises the steps:
Preparation bag carries the liposome of biological compatible metal ion;
In the solution that contains biological available macromolecular material, add bag carry the liposome of biological compatible metal ion and mix, obtain mixed liquor;
By mixed liquor hatching, obtain hydrogel.
8. preparation method as claimed in claim 7, it is characterized in that, the available macromolecular material of described biology comprises the macromolecular material with active aldehyde radical, the described macromolecular material with active aldehyde radical is made as follows: natural macromolecular material is dissolved in to solvent, add oxidant to carry out oxidation reaction, obtain having active aldehydes based high molecular material.
9. preparation method as claimed in claim 8, is characterized in that, described oxidant comprises one or more in potassium chlorate, chromium trioxide, hydrogen peroxide and sodium metaperiodate.
10. preparation method as claimed in claim 7, it is characterized in that, the available macromolecular material of described biology comprises one or more in the macromolecular material that has the macromolecular material of bio-ligand and have active aldehyde radical and bio-ligand, the described macromolecular material that has the macromolecular material of bio-ligand or have active aldehyde radical and a bio-ligand is made as follows: natural macromolecular material or the macromolecular material with active aldehyde radical are dissolved in solvent, regulate pH value, pass into nitrogen, add again bio-ligand, lucifuge reaction, the macromolecular material that obtains thering is the macromolecular material of bio-ligand or there is active aldehyde radical and bio-ligand.
11. preparation methods as claimed in claim 7, it is characterized in that, in the solvent that contains biological available macromolecular material, add bag to carry the liposome of biological compatible metal ion by preset ratio, the bag that described ratio is carried the liposome of biological compatible metal ion according to bag carries release rate in vivo of rate, metal ion and the valence state of metal ion calculates.
12. 1 kinds of hydrogels as claimed in claim 1 are in the application as in biological organization material.
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