CN109836594A - A kind of preparation method and applications of hydrogel, hydrogel - Google Patents
A kind of preparation method and applications of hydrogel, hydrogel Download PDFInfo
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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
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- A61L27/02—Inorganic materials
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- 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
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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
- A61L2400/00—Materials characterised by their function or physical properties
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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Abstract
The present invention relates to a kind of preparation methods of hydrogel comprising following steps: preparing aqueous solution: water and auxiliary material are mixed to form aqueous solution；It prepares suspension: alkali salt and the aqueous solution being mixed to form suspension, and are dissolved in the alkali salt of 30-50% in the aqueous solution；It prepares hydrogel: the suspension and alginate aqueous solution is uniformly mixed to form hydrogel.The invention further relates to a kind of hydrogels and its application method prepared with the preparation method.
Description
Technical field
The present invention relates to the systems of medical field more particularly to a kind of hydrogel being implanted into suitable for organism, the hydrogel
Preparation Method and its application.
Background technique
Hydrogel is a kind of by the sufficiently diluted cross-linking system of water, and the macromolecular structure with three-dimensional network crosslinking contains
There is a large amount of hydrophilic radical, water can be filled in it, so that hydrogel overall mechanical properties are similar to soft tissue.So that
Hydrogel has both property of both solid and liquid, changes the characteristic of own form with response external environment.Hydrogel
It is had the advantages that when as tissue engineering material inside (1) hydrogel containing a large amount of water, effectively maintenance tissue microenvironment
Balance；(2) biocompatibility is good, and tissue irritation is lower；(3) gelatinizing-in-situ or injection fillers arbitrary shape can be passed through
Cavity.The above feature makes hydrogel in biomedicine, such as biological support, cell culture, medicine controlled releasing, biosensor field
It has broad application prospects.
According to the difference of synthetic material, hydrogel is divided into synthesis macromolecule hydrogel and natural polymer hydrogel, wherein
Natural polymer due to better biocompatibility, to the better sensibility of environment and richer source to application compared with
It is extensive.Alginic acid is a kind of important natural polymer, is the naturally-produced polymer of marine organisms, is had in physiology phase
Develop and be formed by curing the unique ability of gel at a temperature of pass, and there is good biocompatibility and non-immunogenicity, does not draw
Human body allosome rejection and allergic reaction are played, therefore can be used to prepare natural polymer hydrogel.In general, alginic acid is by β-D-
Two kinds of monomers of mannuronic acid (M) and α-L- guluronic acid (G) are constituted, and can be converted into the form application of alginate.When one
A divalent alkaline-earth metal ion and negative electrical charge from two different respective G groups of alginate polymer chain formed from
Sub-key, two polymer crosslink, and generation is such multiple cross-linked between many polymer, to generally form cross-linked network
Network, while the chain of these networks contains a large amount of hydrophilic groups, just forms hydrogel.
Injectable for organizational project in biomedicine is implanted into the prerequisite characteristic of material are as follows: structure is uniform, it is nontoxic,
Good biocompatibility, syringeability, suitable viscosity, solidifies rapid and mild condition at biological degradability appropriate, protects
Card injection after stay in the position that need to be filled, in the process should not heat release or heat release it is less avoid damage surrounding tissue, suitable machine
Tool intensity can use conventional method sterilizing etc. to resist pressure in situ.In the prior art, when alginate solution and with Gao Rong
When the alkaline-earth metal salt solution gelling of Xie Du, crosslinking can be immediately occurred in system, generated one layer of high-strength gel in contact surface, formed
A large amount of microballoons, capsule, fibrous hydrogel, internal storage modulus are simultaneously uneven.Therefore, when requiring hydrogel to lead by longer
When the following syringe needle of Guan Bingcong 30G is injected outward, the biggish part of storage modulus can block syringe needle in this gellike, make in the short time
Push pressure increases rapidly, is unfavorable for the injection and implantation of hydrogel.
In addition, there is the demand that hydrogel is prepared in situ in surgical operation or experiment, so that hydrogel to be injected to
Organism, such as the cardiac muscle of human body.The hydrogel being prepared in situ can avoid a series of problems, such as cross contamination.But current
When hydrogel is prepared at the scene, required time is long, is easy delay operation or experimental period.
Summary of the invention
In view of this, the hydrogel of injection and implantation can quickly be prepared it is necessary to provide one kind and being conducive to hydrogel,
The preparation method and applications method of the hydrogel.
To achieve the above object, the present invention provides a kind of method for quickly preparing hydrogel in first aspect comprising
Following steps:
Water and auxiliary material are mixed to form aqueous solution；
Alkali salt and the aqueous solution are mixed to form suspension, and dissolve the alkali salt of 30%-50%
In the aqueous solution；
The suspension and alginate aqueous solution are uniformly mixed to form hydrogel；
Wherein, alginate and alkali salt are salt not of the same race.
Further, the partial size of the alkali salt is greater than 300 microns.
Further, the incorporation time of the alkali salt and the aqueous solution is less than or equal to 1 hour.
Further, the alkali salt be containing magnesium, calcium, strontium, barium alkali salt, the alkali salt
Form is at least one of sulfate, citrate, gluconate, lactate, carbonate, phosphate, alginate.
Further, the alkali salt is 0-25 degrees Celsius with the mixing temperature in the aqueous solution when mixing.
Further, the alkali salt is mixed under isoperibol with the aqueous solution.
Further, the incorporation time of the suspension and alginate aqueous solution is less than or equal to 5 minutes.
Further, the suspension is uniformly mixed by way of manually or mechanically vibrating with alginate aqueous solution.
Further, the hydrogel is for injecting organism, storage modulus of the hydrogel before injecting organism
For the 60%-85% of hydrogel maximum storage modulus.
Further, the suspension is mixing the hydrogel storage modulus formed in 1 minute with alginate aqueous solution
Maximum value be the final storage modulus of hydrogel 60%-85%.
Further, the above-mentioned method for quickly preparing hydrogel further comprises:
The first container, second container, third container and triple valve are provided, the triple valve is capable of the on-off of selectivity；
It prepares alginate aqueous solution and is loaded into the first container；
The aqueous solution that water and auxiliary material are formed is injected into the second container；
Alkali salt is packed into the third container；
The inner air of the first container, the second container and the third container is discharged and connects described three
Port valve, the triple valve make isolated from one another between the first container, the second container and the third container；
When being prepared in situ, the second container and the third reservoir are obtained into the suspension, the institute that will be obtained
Suspension is stated to be pushed into the first container by triple valve.
The present invention provides a kind of hydrogel being prepared with the above-mentioned method for quickly preparing hydrogel in second aspect,
For injecting organism, wherein the hydrogel mixed, be crosslinked with alginate aqueous solution by alkaline-earth metal salt particle, aqueous solution and
At the storage modulus of the hydrogel is the 60%-85% of hydrogel maximum storage modulus.
The present invention provides a kind of application method of hydrogel in the third aspect comprising following steps:
Water and auxiliary material are mixed to form aqueous solution；
Alkali salt and the aqueous solution are mixed to form suspension, and dissolve the alkali salt of 30%-50%
In the aqueous solution；
The suspension and alginate aqueous solution are uniformly mixed to form hydrogel；
Hydrogel is injected into organism.
Further, storage modulus of the hydrogel before injecting organism is that injection organism post-crosslinking reaction is complete
The 60%-85% of maximum storage modulus afterwards.
Further, in preparing hydrogel step, in preparing hydrogel step, the suspension and alginic acid salt water
Solution incorporation time is less than or equal to 5 minutes.
Further, in preparing hydrogel step, in preparing hydrogel step, the suspension and alginic acid salt water
It is after injection organism post-crosslinking reaction is complete that solution is uniformly mixed to form storage modulus within the time less than or equal to 1 minute
The hydrogel of the 60%-85% of maximum storage modulus.
Further, when injecting organism, the temperature of the organism is 35-45 degrees Celsius.
Compared with prior art, the method for quickly preparing hydrogel of the invention, passes through the suspension of alkali salt
It is crosslinked with alginate, reduces the concentration for participating in the alkaline-earth metal salt solution of cross-linking reaction, so that alkaline-earth metal
Salt and alginate not will form a large amount of microballoon, capsule, fibrous hydrogel when being crosslinked, internal storage modulus is more equal
It is even, obtain the hydrogel that syringeability is good and organizes interior retentivity good.In addition, be crosslinked by suspension and alginate,
It is achieved with satisfactory hydrogel in the short period, operation is greatly shortened and experimental field prepares the time of hydrogel.
The hydrogel that hydrogel preparation method through the invention obtains, syringeability is good, can pass through longer lead
Manage and be not easy to plug syringe needle, while also there is suitable mechanical strength, can pressure in situ in resisted organize, stop after guaranteeing injection
Stay in the position that need to be filled.In practical applications, the hydrogel for meeting experiment or operation can be obtained within a short period of time, just
In injecting and being implanted into organism, the risk for delaying experiment or operating time is effectively reduced.
Detailed description of the invention
Fig. 1 is the flow chart that the present invention prepares hydrogel；
Fig. 2 is the storage modulus variation diagram that hydrogel is prepared in the present invention；
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, right with reference to the accompanying drawings and embodiments
The present invention is further elaborated.It should be appreciated that described herein, specific examples are only used to explain the present invention, not
For limiting the present invention.
For the technical term occurred in the present invention, specific explanations are as follows:
Storage modulus (storage modulus) refers to Young's modulus, is the index of material rebounds upon deformation, indicates material
The ability of material storage elastic deformation energy.
Original position pressure refers to muscle or the cell pressure caused by the foreign matter to implant in living tissue in tissue.
Syringeability refers to can be by that compared with long duct and will not block the ability of 30G or less syringe needle.
Retentivity refers to hydrogel in implanting tissue behind a certain position in organizing, and pressure in situ is still in resisted organize
It is maintained at the ability at the position.
As shown in Figure 1, the present invention provides a kind of method for quickly preparing hydrogel comprising following steps:
Step 101, water and auxiliary material are mixed to form aqueous solution.
Step 102, alkali salt and aqueous solution are mixed to form suspension, and make the alkali salt of 30%-50%
It is dissolved in aqueous solution.
Step 103, suspension and alginate aqueous solution are uniformly mixed to form hydrogel.
The alkali salt of 30%-50% is dissolved in aqueous solution in the present invention, refer to dissolution alkali salt with
The total alkali salt being added is 30%-50% compared to shared mass percent, such as the additional amount of alkali salt is
100g, then the amount being dissolved in the water then is 30g-50g.
Referring to table 1, table 1 shows the performance for the hydrogel that different ratio suspension is prepared, wherein the seaweed chosen
Hydrochlorate is sodium alginate, and alkaline-earth metal salt particle is calcium citrate, mainly with retentivity in the syringeability of hydrogel and tissue
As evaluation index.
The performance for the hydrogel that 1 different ratio suspension of table is prepared
By table 1 it is known that the alkali salt when 30%, 40%, 50% is dissolved in aqueous solution, it can guarantee the portion
Homogeneous cross-link quickly occurs for the alkali salt and alginate aqueous solution for dividing dissolution, is substantially completed cross-linking process, obtains structure
Uniformly and the hydrogel with suitable storage modulus, syringeability and the interior retentivity of tissue are preferable.When alkali salt dissolves
Content in aqueous solution is more than above-mentioned numberical range, then cannot obtain the hydrogel of ideal performance.For example, working as alkali salt
Meltage when being 20%, although syringeability is preferable, the attainable storage modulus of institute is lower in a long time, tissue
Interior retentivity is poor.When the meltage of alkali salt is 60%, although retentivity is preferable in organizing, storage modulus value mistake
Height cannot pass through conduit and be easy blocking syringe needle, and syringeability substantially reduces.What preparation method of the invention was prepared
Hydrogel, it is a kind of ideal syringeability that reaction preparation time is short and with retentivity in outstanding syringeability and tissue
Material.
In the of the invention method for quickly preparing hydrogel, by prepare alkali salt suspension and alginate into
Row crosslinking makes the concentration for participating in the alkaline-earth metal salt solution of cross-linking reaction so that alkali salt is partially dissolved in aqueous solution
It reduces, obtains the suspension of suitable solubility, facilitate alginate polymer chain and equably handed over alkaline-earth metal ions
Connection reaction, and the hydrogel that suitable storage modulus and storage modulus are evenly distributed can be obtained in the short period upon mixing.
The hydrogel obtained after preparation can not only pass through compared with long duct and will not block syringe needle, furthermore be planted by conduit and syringe needle
After entering tissue, it will not be squeezed out by the interior pressure in situ of tissue, with outstanding syringeability and organize interior retentivity.
Further, the present invention is crosslinked by the suspension of alkali salt with alginate, is utilizing the present invention
When preparation method prepares hydrogel, the requirement to raw material can be relaxed, for example, in the suspension for preparing alkali salt, it can
Select the alkali salt of 300 microns or more partial sizes.Therefore, the method that hydrogel is prepared in the present invention, manufacture difficulty is lower, fits
It is wider with property.
Wherein, in the preparation process of above-mentioned aqueous solution, water and auxiliary material are not especially limited, and water is preferably deionized nothing
Bacterium water, auxiliary material are preferably at least one of sodium chloride, sorbierite, fructose, mannitol, lactose or Chitosan.Wherein, upper
It states in the preparation process of suspension, alkali salt can be common alkaline-earth metal various salt generated, wherein alkaline-earth metal
Preferably magnesium, calcium, strontium, barium, alkaline earth metal salt are preferably sulfate, citrate, gluconate, lactate, carbonic acid
At least one of salt, phosphate, alginate.Wherein, during preparing hydrogel, alginate aqueous solution is by seaweed
Hydrochlorate and water are prepared, and alginate can be sodium alginate, lithium alginate, potassium alginate etc., and water is preferably deionized
Sterile water.Under certain condition, auxiliary material can be also added in the raw material for preparing alginate aqueous solution, auxiliary material can be but not office
It is limited to one of barium sulfate, tungsten powder, Iopromide, sodium chloride, sorbierite, fructose, mannitol, lactose or Chitosan or several
Kind.
Further, in the preparation process of suspension, the present invention can be used the mode manually or mechanically vibrated and mix system
It is standby, for example, by using stirring or ultrasonic activation, to improve the mixture homogeneity of suspension.Further, in order to avoid alkaline earth gold
Belong to salt dissolution it is excessive, the present invention in the incorporation time of alkali salt and aqueous solution be less than or equal to 1 hour, alkali salt and
The incorporation time of aqueous solution the operative site used time, can be by improving the side such as vibration frequency depending on the solubility of alkali salt
Formula improves the solubility of alkali salt, to shorten the incorporation time of alkali salt and aqueous solution, such as by incorporation time control
System is within 1-10 minutes, under optimal cases, controls within 1 minute, facilitates scene i.e. with i.e. use.Certainly, alkali of the invention
Earth metal salt and aqueous solution can also be prepared in advance, and incorporation time control is less than 24 hours, preferably smaller than 12 hours, thus side
Just scene obtains suspension.But incorporation time is also unsuitable too long, if more than 24 hours, will lead to the molten of alkali salt
Solution spends height, and more than 50%, solution is become to clarify by suspended, thus can be anti-with alginate at once when mixing with alginate
It answers, forms microballoon, capsule or fibrous hydrogel, be unfavorable for obtaining the hydrogel of suitable performance.
Further, the preparation temperature of suspension is set as 0-25 degrees Celsius, preferably 10-25 degrees Celsius.If outstanding
The preparation temperature of turbid is higher than 25 degrees Celsius or is put into the haybox cooking higher than 25 degrees Celsius after preparation, will cause alkaline earth
The meltage of metal salt in aqueous solution is excessive, more than 50%, is stored up so that hydrogel just reacts within a short period of time
Energy modulus is uneven and excessively high hydrogel, hydrogel cannot pass through compared with long duct and be easy blocking 30G or less syringe needle, can infuse
Penetrating property is poor.It should be noted that the temperature or any stationary temperature that change in the temperature range, preferably take the photograph in 0-25
It is mixed under an isoperibol between family name's degree.
The mode mixing suspension manually or mechanically vibrated and alginate can be used in the present invention, for example, by using stirring or surpasses
Acoustic vibration, to improve the mixture homogeneity of suspension.
Since hydrogel of the invention has outstanding syringeability and organizes interior retentivity, and can obtain within a short period of time
The syringeability hydrogel that must be meeted the requirements, therefore, can be applied to surgical operation or experiment in be prepared in situ, can be by water-setting
Glue is for injecting in organism, such as human body or the cardiac muscle of animal, to treat heart failure.Hydrogel of the invention is in injection organism
Before, when the storage modulus of hydrogel is 60%, 72%, 80%, the 85% of hydrogel maximum storage modulus, hydrogel can
Pass through conduit and 30G syringe needle below, be not susceptible to blocking syringe needle, and after being injected into organism, organize in retentivity it is good,
Pressure in situ injection site can be remained in resisted organize.If storage modulus is lower than 60%, led although can pass through
Syringe needle is managed and will not block, but it organizes interior retentivity inadequate.And if storage modulus be higher than 85%, although organize in retentivity
Preferably, but often it is easy blocking syringe needle when injection, is not easy to inject.Therefore, the present invention is by hydrogel in injection organism
Before, the storage modulus of hydrogel is the 60%-85% of hydrogel maximum storage modulus, preferably 80%, which can protect
Card hydrogel will not only block syringe needle in injection and implantation process, but also can preferably keep in vivo.
Further, in the preparation process of hydrogel, the incorporation time of suspension and alginate aqueous solution is smaller than
Equal to 5 minutes, i.e., within 5 minutes time, suspension of the invention and alginate aqueous solution can occur uniformly to hand over
Connection reaction, acquisition storage modulus is moderate, such as the storage modulus of hydrogel is the 60%-85% of the final storage modulus of hydrogel,
With good syringeability and organize in retentivity hydrogel, so as to shorten operation and experimental field prepare hydrogel when
Between, it realizes that matching for hydrogel is used, avoids the cross contamination of hydrogel.
Further, it performs the operation and tests and generally require to obtain the injectable materials to meet the requirements within the short time as far as possible,
It again needs that related personnel is facilitated to operate simultaneously, be wanted so the storage modulus of hydrogel reaches within the relatively short time
It asks, this is more satisfactory.Accordingly, it is considered to which to the convenience i.e. with the i.e. operation of use and related personnel, the present invention is preferably outstanding
For turbid with alginate aqueous solution in 1 minute mixed, the maximum value of the hydrogel storage modulus of formation is that hydrogel is final
The 60%-85% of storage modulus facilitates the injection of hydrogel to realize i.e. with using.
For the ease of preparing hydrogel in aforementioned manners, the present invention also provides the tools for preparing hydrogel.Above-mentioned kit
Include attachment device and three containers, three containers and the equal cleaning sterile of attachment device.Specifically, alginate aqueous solution is packed into
The first container, the first container are preferably syringe；The aqueous solution that water and auxiliary material are formed is injected into second container, second container is preferred
For syringe；Alkali salt is packed into third container, third container is preferably syringe.Above three container is being excluded into sky
By the attachment device, preferably triple valve after gas, it is connected on a conduit and ensures that above three container is isolated from one another,
Wherein the first container and second, third container connection.It in the present invention, can be by alginic acid salt water by the tool of above-mentioned autocracy
Solution, alkali salt and aqueous solution partial volume device stablize storage, realize i.e. with using, facilitate storage and preparation.When needing scene
When preparation, by the second container equipped with aqueous solution and the third container connection equipped with alkali salt and triple valve is closed, such as
Can by the aqueous solution in syringe be pushed into equipped with alkali salt syringe in, or otherwise can also, vibration mixing one timing
Between obtain milky suspension.After suspension is prepared, triple valve is opened within 1 hour, suspension is pushed into and is filled
There is the first container of alginate, is mixed using mechanical oscillation or manually mode and become uniform hydrogel.Wherein, machine
Tool vibration can be ultrasonic activation.Certainly, it according to the difference of the solubility of different alkali salts, can also be appropriately extended suspended
The standing time of liquid is, for example, less than 24 hours, as long as before ensuring that suspension is mixed with alginate aqueous solution, alkali in suspension
The meltage of earth metal salt is 30%-50%.
The present invention also provides a kind of using hydrogel prepared by above-mentioned preparation method, with good bio-compatible
Property, it can be used for injecting organism.The hydrogel is mixed with alginate aqueous solution by alkaline-earth metal salt particle, aqueous solution, is handed over
Join.Alkaline-earth metal salt particle and aqueous solution can first be mixed to get the suspension for having dissolved part alkaline-earth metal salt particle, side
Just crosslinking is mixed with alginate aqueous solution obtains the hydrogel that syringeability is good and organizes interior retentivity good.Wherein alkaline earth gold
The partial size for belonging to salt particle can be greater than general partial size in the prior art, such as can be more than or equal to 300 microns.Further, water-setting
The storage modulus of glue is the 60%-85% of the final storage modulus of hydrogel, which can most preferably guarantee that hydrogel exists
Will not only syringe needle have been blocked in injection and implantation process but also can be stably maintained in organism.
Compared with prior art, hydrogel structure of the invention is uniform, has suitable storage modulus, injection and implantation
Injection phase that is very convenient, and being preferably maintained in tissue.
The present invention also provides a kind of application methods of hydrogel comprising following steps: water and auxiliary material are mixed to form water
Solution；Alkali salt and the aqueous solution are mixed to form suspension, and the alkali salt of 30%-50% is made to be dissolved in institute
It states in aqueous solution；The suspension and alginate aqueous solution are uniformly mixed to form hydrogel, finally by the hydrogel of acquisition
Organism is injected by conduit.It is mixed by suspension with alginate aqueous solution, the present invention can be closed within a short period of time
Require syringeability hydrogel, therefore, can be applied to surgical operation or experiment in be prepared in situ.
Further, hydrogel of the invention is before injecting organism, when the storage modulus of hydrogel is that hydrogel is maximum
Storage modulus 60%, 72%, 80%, 85% when, hydrogel can pass through conduit and 30G syringe needle below, be not easy
Blocking syringe needle occurs, and after being injected into organism, organize in retentivity it is good, pressure in situ can remain at note in resisted organize
Penetrate position.If storage modulus is lower than 60%, although can pass through conduit and will not block syringe needle, it organizes interior keep
Property is inadequate.And if storage modulus is higher than 85%, although retentivity is preferable in organizing, blocking needle is often easy when injection
Head is not easy to inject.Therefore, for the present invention by hydrogel before injecting organism, the storage modulus of hydrogel is the storage of hydrogel maximum
The 60%-85% of energy modulus, preferably 80%, which can guarantee that hydrogel will not both block up in injection and implantation process
Syringe needle is filled in, and can preferably be kept in vivo.
Further, it performs the operation and tests and generally require to be closed within the time that is as short as possible and facilitating related personnel to operate
Desired injectable materials, so the storage modulus of hydrogel reaches requirement within the corresponding time, this is more satisfactory.
Accordingly, it is considered to which the preferred suspension of the present invention and alginate are water-soluble to the convenience i.e. with the i.e. operation of use and related personnel
Liquid incorporation time is less than or equal to can be obtained for 5 minutes that storage modulus is moderate, and the storage modulus of preferred hydrogel is that hydrogel is maximum
The 60%-85% of storage modulus is realized with good syringeability and the hydrogel for organizing interior retentivity and is matched i.e. use.More
Preferably, suspension of the invention is with alginate aqueous solution in the maximum for mixing the hydrogel storage modulus formed in 1 minute
Value is the 60%-85% of the final storage modulus of hydrogel.
Further, the preparation process of hydrogel can carry out in certain temperature range, such as the temperature prepared is in 0-25
In degree Celsius range.Certainly, the organism for injecting hydrogel can be higher than above-mentioned preparation temperature, such as the temperature of organism can be
35-45 degrees Celsius.Temperature has differences between preparation temperature and the temperature of organism, can pass through hydrogel preparation process in this way
It neutralizes injection organism and there is temperature difference between the two, so that promoting hydrogel in vivo after hydrogel injection organism
Reaction is crosslinked, is conducive to just reach maximum storage modulus in the time shorter in vivo, saves operation and experiment
Time.
The present invention can be obtained the injection aquagel material to meet the requirements within a short period of time, and it is convenient to obtain, and subtract significantly
The small risk for delaying experiment or operating time can be applied in experiment or surgical operation be prepared in situ.Lead to when by hydrogel
When crossing compared with long duct and injecting outward from smaller such as 30G or less syringe needle, the hydrogel that preparation method of the present invention obtains can be suitable
Benefit is by conduit and syringe needle, specifically, in practical applications, can be used in various specific Transmission systems, such as biomedicine
Implantation in situ, tissue filling, embolism forms operation, anti-adhesion therapies, treatment of wounds, and preparation is in vitro or in-vivo tissue building
Object, treating diabetes, the coating etc. of implanted device.
Compared with prior art, in the application method of hydrogel of the invention, pass through the suspension of alkali salt
The hydrogel obtained with alginate aqueous solution cross-linking reaction, so that there is hydrogel good syringeability and tissue to keep
Property, and the syringeability hydrogel to meet the requirements can be obtained within a short period of time, meet the requirement of organism injection, application range
Extensively.
As shown in Fig. 2, making further to subject hydrogel and preparation method thereof below in conjunction with specific embodiments
Explanation.Since syringeability, tissue retentivity are related to the storage modulus of hydrogel, this part is mainly to hydrogel energy storage
The variation of modulus keeps a record.
Embodiment 1
Preparation temperature is set as 0-25 degrees Celsius
Step (1) determines that alginate group is divided into the aqueous solution of sodium alginate, mannitol, and alkali salt group is divided into lemon
Lemon acid calcium, aqueous composition are water and mannitol.
Step (2), the preparation of sodium alginate component: 2g mannitol and 3g sodium alginate are dissolved in 100g water, and stirring is extremely
All dissolutions.
The preparation of aqueous composition: 3.8g mannitol is dissolved in 100g water for step (3).
Step (4) fills sample: taking first syringe of 3 milliliters of maximum scale, the first syringe is connected to one three
In port valve.It takes out the piston of the first syringe and closes triple valve.0.021 gram of calcium citrate is packed into the first syringe, is beaten
It opens triple valve connection air and piston is put back into the first syringe, citric acid is left behind after the air being discharged in the first syringe
Calcium powder closes triple valve.0.5 milliliter of aqueous solution is taken with second syringe and accesses threeway after emptying its front end air
Valve.It is pumped into 1 milliliter of sodium alginate component with third branch syringe, triple valve is connected after the air in exhaustjet device.
Step (5), hydrogel preparation: will be equipped with two syringe connection of aqueous solution and calcium citrate powder, will be water-soluble
Syringe of the liquid push-in equipped with calcium citrate powder simultaneously closes triple valve.Vibration mixing obtains milky suspension in 5 minutes, hangs
The calcium citrate dissolved in turbid is 30%.Triple valve is opened in 12 hours, and suspension push-in is equipped with sodium alginate aqueous solution
Syringe, mix it uniformly.
Hydrogel is carried out the test of storage modulus by step (6).
The variation of the storage modulus of the hydrogel refers to the chart of Fig. 2, and ordinate indicates storage modulus on the left of chart, with
G ' indicates that unit Pa, abscissa indicates time, unit min.The present embodiment finally obtains uniformly mixed hydrogel, surveys
Examination as the result is shown by suspension push-in equipped with sodium alginate aqueous solution syringe after, hydrogel reaches in 1 minute
Storage modulus be 4000pa, the storage modulus is moderate, and storage modulus is 80% or so of final storage modulus, and hydrogel is logical
When crossing compared with long duct and injecting outward from 30G or less syringe needle, syringe needle will not be blocked, and organizes interior retentivity excellent.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (17)
1. a kind of method for quickly preparing hydrogel comprising following steps:
Water and auxiliary material are mixed to form aqueous solution；
Alkali salt and the aqueous solution are mixed to form suspension, and the alkali salt of 30%-50% is made to be dissolved in institute
It states in aqueous solution；
The suspension and alginate aqueous solution are uniformly mixed to form hydrogel；
Wherein, alginate and alkali salt are salt not of the same race.
2. the method for quickly preparing hydrogel as described in claim 1, which is characterized in that the partial size of the alkali salt is big
In 300 microns.
3. the method for quickly preparing hydrogel as described in claim 1, which is characterized in that the alkali salt and the water
The incorporation time of solution is less than or equal to 1 hour.
4. as described in claim 1 quickly prepare hydrogel method, which is characterized in that the alkali salt be containing
Magnesium, calcium, strontium, barium alkali salt, the form of the alkali salt is sulfate, citrate, gluconate, lactic acid
At least one of salt, carbonate, phosphate, alginate.
5. the method for quickly preparing hydrogel as described in claim 1, which is characterized in that the alkali salt and the water
Mixing temperature of the solution in mixing is 0-25 degrees Celsius.
6. the method for quickly preparing hydrogel as claimed in claim 5, which is characterized in that the alkali salt and the water
Solution is mixed under isoperibol.
7. the method for quickly preparing hydrogel as described in claim 1, which is characterized in that the suspension and alginic acid salt water
The incorporation time of solution is less than or equal to 5 minutes.
8. the method for quickly preparing hydrogel as claimed in claim 7, which is characterized in that the suspension and alginic acid salt water
Solution is uniformly mixed by way of manually or mechanically vibrating.
9. the method for quickly preparing hydrogel as described in claim 1, which is characterized in that the hydrogel is for injecting biology
Body, storage modulus of the hydrogel before injecting organism are the 60%-85% of hydrogel maximum storage modulus.
10. the method for quickly preparing hydrogel as described in claim 1, which is characterized in that the suspension and alginate
The maximum value for the hydrogel storage modulus that aqueous solution is formed in mixing 1 minute is the 60%- of the final storage modulus of hydrogel
85%.
11. the method for quickly preparing hydrogel as described in claim 1, which is characterized in that further comprise: providing first and hold
Device, second container, third container and triple valve, the triple valve are capable of the on-off of selectivity；
It prepares alginate aqueous solution and is loaded into the first container；
The aqueous solution that water and auxiliary material are formed is injected into the second container；
Alkali salt is packed into the third container；
The inner air of the first container, the second container and the third container is discharged and connects the threeway
Valve, the triple valve make isolated from one another between the first container, the second container and the third container；
When being prepared in situ, the second container and the third reservoir are obtained into the suspension, it is described outstanding by what is obtained
Turbid is pushed into the first container by triple valve.
12. a kind of hydrogel uses prepared by method of any of claims 1-11, for injecting organism,
It is characterized in that, it is mixed with alginate aqueous solution by alkaline-earth metal salt particle, aqueous solution, is crosslinked, the hydrogel
Storage modulus is the 60%-85% of the final storage modulus of hydrogel.
13. a kind of application method of hydrogel comprising following steps:
Water and auxiliary material are mixed to form aqueous solution；
Alkali salt and the aqueous solution are mixed to form suspension, and the alkali salt of 30%-50% is made to be dissolved in institute
It states in aqueous solution；
The suspension and alginate aqueous solution are uniformly mixed to form hydrogel；
Hydrogel is injected into organism.
14. the application method of hydrogel as claimed in claim 13, which is characterized in that the hydrogel is before injecting organism
Storage modulus be inject organism post-crosslinking reaction it is complete after maximum storage modulus 60%-85%.
15. the application method of hydrogel as claimed in claim 13, which is characterized in that described in preparing hydrogel step
Suspension and alginate aqueous solution incorporation time are less than or equal to 5 minutes.
16. the application method of hydrogel as claimed in claim 13, which is characterized in that described in preparing hydrogel step
Suspension and alginate aqueous solution are uniformly mixed to form storage modulus within the time less than or equal to 1 minute as injection organism
The hydrogel of the 60%-85% of maximum storage modulus after post-crosslinking reaction is complete.
17. the application method of hydrogel as claimed in claim 13, which is characterized in that when injection organism, the organism
Temperature be 35-45 degrees Celsius.
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| CN114699364B (en) * | 2022-03-29 | 2023-06-27 | 山东大学 | Alginate injectable hydrogel and preparation method and application thereof |
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| CN114015073A (en) | 2022-02-08 |
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