CN114015073A

CN114015073A - Hydrogel for injecting organisms and application thereof

Info

Publication number: CN114015073A
Application number: CN202111149966.8A
Authority: CN
Inventors: 郑吉�; 邵南; 张里斯
Original assignee: Deke Medtech (hangzhou) Inc
Current assignee: Deke Medtech (hangzhou) Inc
Priority date: 2017-11-24
Filing date: 2017-11-24
Publication date: 2022-02-08
Anticipated expiration: 2037-11-24
Also published as: CN109836594A; CN109836594B; CN114015073B

Abstract

The invention relates to a hydrogel for injecting organisms and application thereof, wherein the hydrogel is formed by mixing and crosslinking alkaline earth metal salt, an aqueous solution containing auxiliary materials and an alginate aqueous solution in a constant temperature environment, and the storage modulus of the hydrogel is 60-85% of the final storage modulus of the hydrogel; the alkaline earth metal salt is alkaline earth metal salt containing magnesium, calcium, strontium and barium, and the form of the alkaline earth metal salt is at least one of sulfate, citrate, gluconate, lactate, carbonate, phosphate and alginate. The hydrogel disclosed by the invention is good in injectability, can smoothly pass through a longer catheter, is not easy to block a needle head, has appropriate mechanical strength, can resist in-situ pressure in tissues, and can be guaranteed to stay at a position to be filled after injection.

Description

Hydrogel for injecting organisms and application thereof

The application is a divisional application of invention creation title of 'hydrogel, preparation method of hydrogel and application thereof', the application date of the original application is 11/24/2017, and the application number of the original application is 201711195532.5.

Technical Field

The invention relates to the field of medical treatment, in particular to hydrogel suitable for organism implantation, a preparation method and application thereof.

Background

The hydrogel is a crosslinking system fully diluted by water, has a three-dimensional network crosslinked high molecular structure, contains a large number of hydrophilic groups, and can be filled with water, so that the overall mechanical property of the hydrogel is similar to that of soft tissues. Thus, the hydrogel has both solid and liquid properties and has the characteristic of changing its shape in response to the external environment. The hydrogel has the following advantages when being used as a tissue engineering material: (1) the hydrogel contains a large amount of water, so that the micro-environment balance of tissues is effectively maintained; (2) the biocompatibility is good, and the tissue irritation is low; (3) cavities of any shape can be gelled in situ or filled by injection. The characteristics lead the hydrogel to have wide application prospect in the fields of biomedicine, such as biological stents, cell culture, drug controlled release, biosensors and the like.

According to the difference of synthetic materials, the hydrogel is divided into synthetic polymer hydrogel and natural polymer hydrogel, wherein the natural polymer has wider application due to better biocompatibility, better sensitivity to environment and richer sources. Alginic acid is an important natural polymer, is a polymer naturally produced by marine organisms, has unique capability of developing and curing at physiologically relevant temperatures to form gel, has good biocompatibility and no immunogenicity, does not cause human body rejection and anaphylactic reaction, and can be used for preparing natural polymer hydrogel. Generally, alginic acid is composed of two monomers, β -D-mannuronic acid (M) and α -L-guluronic acid (G), and can be converted into alginate for use. When a divalent alkaline earth metal ion forms an ionic bond with the negative charge from a G group on each of two different alginate polymer chains, the two polymers crosslink, such multiple crosslinks occur between many of the polymers, thereby forming a crosslinked network as a whole, and the chains of the network contain a large number of hydrophilic groups, forming a hydrogel.

Injectable implant materials for tissue engineering in biomedicine must possess the following properties: uniform structure, no toxicity, good biocompatibility, proper biodegradability, injectability, proper viscosity, rapid curing and mild conditions, ensures that the injection product is left at a position to be filled, does not release heat or releases less heat to avoid damaging surrounding tissues in the process, has proper mechanical strength to resist in-situ pressure, can be sterilized by a conventional method and the like. In the prior art, when an alginate solution and an alkaline earth metal salt solution with high solubility are gelled, the system can be crosslinked immediately, a layer of high-strength gel is generated on a contact surface, a large number of microspheres, capsules and fibrous hydrogel are formed, and the internal storage modulus is not uniform. Therefore, when hydrogel is required to pass through a longer catheter and injected from a needle below 30G, the needle is blocked by the part of the gel with higher storage modulus, so that the pushing pressure is rapidly increased in a short time, which is not favorable for hydrogel injection and implantation.

Furthermore, there is a need for preparing hydrogels on site at the time of surgery or experiment in order to inject the hydrogels into the myocardium of a living body, such as a human body. The hydrogel prepared on site can avoid a series of problems such as cross contamination and the like. However, the current hydrogel is prepared in situ, which requires a long time and easily delays the operation or experiment time.

Disclosure of Invention

In view of the above, there is a need for a hydrogel that can be rapidly prepared and facilitates injection and implantation of the hydrogel, a method for preparing the hydrogel, and a method for using the hydrogel.

To achieve the above object, the present invention provides in a first aspect a method for rapidly preparing a hydrogel, comprising the steps of:

mixing water and auxiliary materials to form an aqueous solution;

mixing alkaline earth metal salt with the aqueous solution to form a suspension, and dissolving 30-50% of the alkaline earth metal salt in the aqueous solution;

uniformly mixing the suspension with an alginate aqueous solution to form hydrogel;

wherein, the alginate and the alkaline earth metal salt are different salts.

Further, the particle size of the alkaline earth metal salt is greater than 300 microns.

Further, the mixing time of the alkaline earth metal salt and the aqueous solution is 1 hour or less.

Further, the alkaline earth metal salt is alkaline earth metal salt containing magnesium, calcium, strontium and barium, and the form of the alkaline earth metal salt is at least one of sulfate, citrate, gluconate, lactate, carbonate, phosphate and alginate.

Further, the mixing temperature of the alkaline earth metal salt and the aqueous solution at the time of mixing is 0 to 25 ℃.

Further, the alkaline earth metal salt is mixed with the aqueous solution under a constant temperature environment.

Further, the mixing time of the suspension and the alginate aqueous solution is less than or equal to 5 minutes.

Further, the turbid liquid and the alginate water solution are uniformly mixed in a manual or mechanical vibration mode.

Further, the hydrogel is used for injecting organisms, and the storage modulus of the hydrogel before the hydrogel is injected into the organisms is 60% -85% of the maximum storage modulus of the hydrogel.

Further, the maximum value of the hydrogel storage modulus formed by mixing the suspension and the alginate aqueous solution in 1 minute is 60-85% of the final storage modulus of the hydrogel.

Further, the method for rapidly preparing a hydrogel further comprises:

providing a first container, a second container, a third container and a three-way valve, wherein the three-way valve can be selectively switched on and off;

preparing an alginate water solution and filling the alginate water solution into the first container;

injecting an aqueous solution of water and adjuvant into the second container;

charging the third container with an alkaline earth metal salt;

discharging the internal air of the first container, the second container, and the third container and connecting the three-way valve, which blocks the first container, the second container, and the third container from each other;

and during on-site preparation, communicating the second container with the third container to obtain the turbid liquid, and pushing the obtained turbid liquid into the first container through a three-way valve.

The invention provides a hydrogel prepared by the method for quickly preparing the hydrogel, which is used for injecting organisms, wherein the hydrogel is formed by mixing and crosslinking alkaline earth metal salt particles, an aqueous solution and an alginate aqueous solution, and the storage modulus of the hydrogel is 60-85% of the maximum storage modulus of the hydrogel.

The present invention provides, in a third aspect, a method of using a hydrogel, comprising the steps of:

mixing water and auxiliary materials to form an aqueous solution;

the hydrogel is injected into the organism.

Further, the storage modulus of the hydrogel before being injected into an organism is 60% -85% of the maximum storage modulus after the crosslinking reaction is completed after the hydrogel is injected into the organism.

Further, in the step of preparing the hydrogel, the time for mixing the suspension and the alginate aqueous solution in the step of preparing the hydrogel is less than or equal to 5 minutes.

Further, in the step of preparing hydrogel, the suspension and the alginate aqueous solution are uniformly mixed within 1 minute or less to form hydrogel with the storage modulus of 60-85% of the maximum storage modulus after the hydrogel is injected into organisms and the crosslinking reaction is completed.

Further, when the biological body is injected, the temperature of the biological body is 35-45 ℃.

Compared with the prior art, the method for rapidly preparing the hydrogel has the advantages that the concentration of the alkaline earth metal salt solution participating in the crosslinking reaction is reduced by crosslinking the suspension of the alkaline earth metal salt and the alginate, so that a large amount of microspheres, capsules and fibrous hydrogel cannot be formed when the alkaline earth metal salt and the alginate are crosslinked, the internal storage modulus is more uniform, and the hydrogel with good injectability and good tissue retentivity is obtained. In addition, the suspension and the alginate are crosslinked, so that hydrogel meeting the requirements can be obtained in a short time, and the time for preparing hydrogel in operation and experiment sites is greatly shortened.

The hydrogel prepared by the hydrogel preparation method disclosed by the invention is good in injectability, can smoothly pass through a longer catheter, is not easy to block a needle head, has appropriate mechanical strength, can resist in-situ pressure in tissues, and can be guaranteed to stay at a position to be filled after injection. In practical application, the hydrogel meeting the experiment or operation can be obtained in a short time, so that the injection and implantation of organisms are facilitated, and the risk of delaying the experiment or operation time is effectively reduced.

Drawings

FIG. 1 is a flow chart of the present invention for preparing a hydrogel;

FIG. 2 is a graph showing the change in storage modulus of a hydrogel prepared according to the present invention;

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

For technical terms appearing in the present invention, the following is specifically explained:

storage modulus (young modulus) is an index of the resilience of a material after deformation, and represents the ability of the material to store elastic deformation energy.

In situ pressure in a tissue refers to the pressure of muscles or cells in a living tissue against a foreign body implanted in the body.

Syringeability refers to the ability to pass through a longer catheter without clogging the needle below 30 gauge.

By tissue retention is meant the ability of the hydrogel, after implantation at a site in tissue, to remain at the site against in situ pressure within the tissue.

As shown in fig. 1, the present invention provides a method for rapidly preparing a hydrogel, which comprises the steps of:

step 101, mixing water with adjuvants to form an aqueous solution.

102, mixing the alkaline earth metal salt with the aqueous solution to form a suspension, and dissolving 30-50% of the alkaline earth metal salt in the aqueous solution.

And 103, uniformly mixing the suspension with an alginate aqueous solution to form hydrogel.

In the invention, 30-50% of the alkaline earth metal salt is dissolved in the aqueous solution, which means that the mass percentage of the dissolved alkaline earth metal salt is 30-50% compared with the total alkaline earth metal salt added, for example, the addition amount of the alkaline earth metal salt is 100g, and the amount of the dissolved alkaline earth metal salt is 30-50 g.

Referring to table 1, table 1 shows the properties of the hydrogel prepared from suspensions in different ratios, wherein the selected alginate is sodium alginate, the alkaline earth metal salt particles are calcium citrate, and the injectability and tissue retentivity of the hydrogel are mainly used as evaluation indexes.

TABLE 1 Properties of hydrogels prepared from suspensions of different ratios

Amount of alkaline earth metal salt dissolved (% by mass)	Injectability	Retention in tissue
			20	Good taste	Difference (D)
30	Good taste	Good taste
			40	Good taste	Good taste
50	Good taste	Good taste
			60	Difference (D)	Good taste

As can be seen from Table 1, when 30%, 40% or 50% of the alkaline earth metal salt is dissolved in the aqueous solution, uniform crosslinking can be rapidly ensured between the partially dissolved alkaline earth metal salt and the alginate aqueous solution, the crosslinking process is substantially completed, the hydrogel with a uniform structure and a proper storage modulus is obtained, and the injectability and the tissue retention are good. When the content of the alkaline earth metal salt dissolved in the aqueous solution exceeds the above numerical range, a hydrogel having desired properties cannot be obtained. For example, when the amount of the alkaline earth metal salt dissolved is 20%, although injectability is good, the storage modulus that can be achieved over a long period of time is low, and retention in the tissue is poor. When the dissolution amount of the alkaline earth metal salt is 60%, although the retention in the tissue is good, the energy storage modulus value is too high, the salt cannot smoothly pass through the catheter and easily blocks the needle, and the injectability is greatly reduced. The hydrogel prepared by the preparation method has short reaction preparation time, excellent injectability and tissue retention, and is an ideal injectable material.

In the method for rapidly preparing the hydrogel, the suspension of the alkaline earth metal salt is prepared and is crosslinked with the alginate, so that the alkaline earth metal salt is partially dissolved in the aqueous solution, the concentration of the alkaline earth metal salt solution participating in the crosslinking reaction is reduced, the suspension with proper solubility is obtained, the alginate polymer chain is favorably and uniformly subjected to the crosslinking reaction with the alkaline earth metal ions, and the hydrogel with proper storage modulus and uniform storage modulus distribution can be obtained in a short time after mixing. The hydrogel obtained after preparation can smoothly pass through a long catheter without blocking a needle, and can not be extruded by in-situ pressure in tissues after being implanted into the tissues through the catheter and the needle, so that the hydrogel has excellent injectability and in-tissue retention.

Further, in the present invention, the hydrogel is produced by crosslinking the suspension of the alkaline earth metal salt with the alginate, and the requirement for the raw material can be relaxed in the production of the hydrogel by the production method of the present invention, and for example, in the production of the suspension of the alkaline earth metal salt, the alkaline earth metal salt having a particle size of 300 μm or more can be selected. Therefore, the method for preparing the hydrogel has lower manufacturing difficulty and wider applicability.

Wherein, in the preparation process of the aqueous solution, water and auxiliary materials are not particularly limited, the water is preferably deionized sterile water, and the auxiliary materials are preferably at least one of sodium chloride, sorbitol, fructose, mannitol, lactose or chitosan. In the preparation process of the suspension, the alkaline earth metal salt may be any salt generated from common alkaline earth metals, wherein the alkaline earth metal is preferably magnesium, calcium, strontium, and barium, and the form of the alkaline earth metal salt is preferably at least one of sulfate, citrate, gluconate, lactate, carbonate, phosphate, and alginate. Wherein, in the process of preparing the hydrogel, the alginate aqueous solution is prepared from alginate and water, the alginate can be sodium alginate, lithium alginate, potassium alginate and the like, and the water is preferably deionized sterile water. Under certain conditions, auxiliary materials can be added into the raw materials for preparing the alginate aqueous solution, and the auxiliary materials can be one or more of barium sulfate, tungsten powder, iopromide, sodium chloride, sorbitol, fructose, mannitol, lactose or chitosan.

Further, during the preparation of the suspension, the present invention may be prepared by mixing by means of manual or mechanical vibration, such as stirring or ultrasonic vibration, to improve the mixing uniformity of the suspension. Furthermore, in order to avoid excessive dissolution of the alkaline earth metal salt, the mixing time of the alkaline earth metal salt and the aqueous solution is less than or equal to 1 hour, the mixing time of the alkaline earth metal salt and the aqueous solution depends on the solubility of the alkaline earth metal salt, and the solubility of the alkaline earth metal salt can be improved by improving the vibration frequency and the like when the device is used in a surgical field, so that the mixing time of the alkaline earth metal salt and the aqueous solution is shortened, for example, the mixing time is controlled within 1-10 minutes, and is optimally controlled within 1 minute, so that the device is convenient to prepare and use on site. Of course, the alkaline earth metal salt and the aqueous solution of the present invention may be prepared in advance, and the mixing time is controlled to be less than 24 hours, preferably less than 12 hours, thereby facilitating the on-site obtaining of the suspension. However, the mixing time is not necessarily too long, and if it is longer than 24 hours, the solubility of the alkaline earth metal salt is too high, and more than 50%, and the solution becomes clear from suspension, and when it is mixed with the alginate, it reacts with the alginate immediately to form microspheres, capsules, or fibrous hydrogel, which is not favorable for obtaining hydrogel with proper performance.

Further, the preparation temperature of the suspension is set to 0 to 25 degrees centigrade, preferably 10 to 25 degrees centigrade. If the preparation temperature of the suspension is higher than 25 ℃ or the suspension is placed into an incubator higher than 25 ℃ for heat preservation after preparation, the dissolution amount of the alkaline earth metal salt in the aqueous solution is too large and exceeds 50%, so that the hydrogel can react in a short time to obtain hydrogel with uneven and too high storage modulus, the hydrogel can not smoothly pass through a long catheter and easily blocks a needle below 30G, and the injectability is poor. It should be noted that the temperature may be varied within the temperature range or any constant temperature, and preferably the mixing is performed in a constant temperature environment between 0-25 degrees celsius.

The present invention can mix the suspension and alginate by manual or mechanical vibration, such as stirring or ultrasonic vibration, to improve the mixing uniformity of the suspension.

Since the hydrogel of the present invention has excellent injectability and tissue-retentivity and can obtain a desirable injectable hydrogel in a short period of time, it can be applied to on-site preparation in surgery or experiments, and can be used for injection into the cardiac muscle of a living body, such as a human or an animal, to treat heart failure. Before the hydrogel is injected into an organism, when the storage modulus of the hydrogel is 60%, 72%, 80% and 85% of the maximum storage modulus of the hydrogel, the hydrogel can smoothly pass through a catheter and a needle below 30G, the needle is not easy to block, and after the hydrogel is injected into the organism, the tissue retentivity is good, and the in-situ pressure in the tissue can be resisted and still kept at an injection part. If the storage modulus is less than 60%, the retention in the tissue is insufficient although the catheter can pass through the catheter smoothly without clogging the needle. If the energy storage modulus is higher than 85%, although the tissue retention is good, the needle is easy to block during injection, and the injection is difficult. Therefore, before the hydrogel is injected into an organism, the storage modulus of the hydrogel is 60% -85%, preferably 80% of the maximum storage modulus of the hydrogel, and the storage modulus can ensure that the hydrogel can not block a needle in the injection and implantation processes and can be well kept in the organism.

Further, in the preparation process of the hydrogel, the mixing time of the suspension and the alginate aqueous solution can be less than or equal to 5 minutes, namely within 5 minutes, the suspension and the alginate aqueous solution can generate uniform crosslinking reaction, and the hydrogel with moderate storage modulus, such as 60% -85% of the final storage modulus of the hydrogel, and good injectability and tissue internal retentivity is obtained, so that the time for preparing the hydrogel in an operation and experiment site is shortened, the hydrogel is prepared and used immediately, and the cross contamination of the hydrogel is avoided.

Further, surgery and experimentation often requires that a desirable injectable material be obtained in as short a time as possible, while also facilitating handling by the relevant personnel, so that the storage modulus of the hydrogel is desirable in a relatively short time. Therefore, in consideration of instant use and convenience of operation of related personnel, the invention preferably realizes instant use and convenient hydrogel injection by forming the maximum value of the storage modulus of the hydrogel to be 60-85% of the final storage modulus of the hydrogel within 1 minute of mixing of the suspension and the alginate aqueous solution.

In order to facilitate the preparation of hydrogels by the above-described methods, the present invention also provides means for preparing hydrogels. The tool comprises a connecting device and three containers, wherein the three containers and the connecting device are clean and sterile. Specifically, the alginate solution is filled into a first container, preferably a syringe; injecting an aqueous solution of water and adjuvant into a second container, preferably a syringe; the alkaline earth metal salt is charged to a third container, which is preferably a syringe. The three containers are connected to a conduit after air removal by the connecting means, preferably a three-way valve, and ensure that the three containers are isolated from each other, wherein the first container is in communication with the second and third containers. In the invention, the alginate aqueous solution, the alkaline earth metal salt and the aqueous solution can be stably stored in containers by the special tool, so that the instant use after preparation is realized, and the storage and the preparation are convenient. When the preparation is required on site, the second container containing the aqueous solution and the third container containing the alkaline earth metal salt are communicated and the three-way valve is closed, for example, the aqueous solution in the syringe can be pushed into the syringe containing the alkaline earth metal salt, or vice versa, and the mixture is vibrated for a certain time to obtain milky white suspension. After the suspension is prepared, the three-way valve is opened within 1 hour, the suspension is pushed into the first container filled with alginate, and the suspension is mixed by adopting a mechanical vibration mode or a manual mode to form uniform hydrogel. Wherein the mechanical vibration may be ultrasonic vibration. Of course, depending on the solubility of the alkaline earth metal salt, the time for which the suspension is allowed to stand may be appropriately extended, for example, less than 24 hours, as long as the amount of the alkaline earth metal salt dissolved in the suspension is 30% to 50% before mixing the suspension with the alginate aqueous solution.

The invention also provides the hydrogel prepared by the preparation method, which has good biocompatibility and can be used for injecting organisms. The hydrogel is formed by mixing and crosslinking alkaline earth metal salt particles, an aqueous solution and an alginate aqueous solution. The alkaline earth metal salt particles and the aqueous solution can be mixed firstly to obtain suspension in which part of the alkaline earth metal salt particles are dissolved, and the suspension is conveniently mixed with the alginate aqueous solution for crosslinking to obtain hydrogel with good injectability and good tissue retentivity. The particle size of the alkaline earth metal salt particles can be larger than that typical in the prior art, for example, 300 microns or larger. Further, the hydrogel has a storage modulus of 60% to 85% of the final storage modulus of the hydrogel, which is optimal to ensure that the hydrogel will not block the needle during injection and implantation and remain stably in the body.

Compared with the prior art, the hydrogel has a uniform structure, has a proper storage modulus, is very convenient to inject and implant, and can be better kept at an injection position in tissues.

The invention also provides an application method of the hydrogel, which comprises the following steps: mixing water and auxiliary materials to form an aqueous solution; mixing alkaline earth metal salt with the aqueous solution to form a suspension, and dissolving 30-50% of the alkaline earth metal salt in the aqueous solution; and uniformly mixing the suspension with an alginate aqueous solution to form hydrogel, and finally injecting the obtained hydrogel into an organism through a catheter. By mixing the suspension with an aqueous alginate solution, the present invention can obtain a desirable injectable hydrogel in a short time, and thus, it can be applied to on-site preparation in surgery or experiments.

Furthermore, before the hydrogel is injected into organisms, when the storage modulus of the hydrogel is 60%, 72%, 80% and 85% of the maximum storage modulus of the hydrogel, the hydrogel can smoothly pass through a catheter and a needle below 30G, the needle is not easy to block, and after the hydrogel is injected into organisms, the tissue retentivity is good, and the in-situ pressure in the tissue can be resisted and still kept at the injection site. If the storage modulus is less than 60%, the retention in the tissue is insufficient although the catheter can pass through the catheter smoothly without clogging the needle. If the energy storage modulus is higher than 85%, although the tissue retention is good, the needle is easy to block during injection, and the injection is difficult. Therefore, before the hydrogel is injected into an organism, the storage modulus of the hydrogel is 60% -85%, preferably 80% of the maximum storage modulus of the hydrogel, and the storage modulus can ensure that the hydrogel can not block a needle in the injection and implantation processes and can be well kept in the organism.

Further, surgery and experimentation often require that a desirable injectable material be obtained in as short a time as possible and convenient for the relevant personnel to handle, so that the storage modulus of the hydrogel is as desired in a corresponding time, which is desirable. Therefore, in consideration of instant use and convenience of operation of related personnel, the invention preferably selects that the mixing time of the suspension and the alginate aqueous solution is less than or equal to 5 minutes to obtain the hydrogel with moderate storage modulus, preferably the storage modulus of the hydrogel is 60-85% of the maximum storage modulus of the hydrogel, and the hydrogel has good injectability and tissue retentivity, thereby realizing instant use. More preferably, the maximum value of the storage modulus of the hydrogel formed by mixing the suspension of the invention with the aqueous alginate solution within 1 minute is 60-85% of the final storage modulus of the hydrogel.

Further, the hydrogel can be prepared at a temperature in the range of, for example, 0-25 degrees Celsius. Of course, the temperature of the organism into which the hydrogel is injected may be higher than the above preparation temperature, for example, the temperature of the organism may be 35-45 degrees Celsius. The temperature difference exists between the preparation temperature and the temperature of the organism, so that the temperature difference exists between the hydrogel preparation process and the injected organism, the hydrogel is promoted to generate a crosslinking reaction in the organism after being injected into the organism, the maximum storage modulus can be reached in a short time in the organism, and the operation and experiment time is saved.

The invention can obtain the required injectable hydrogel material in a short time, is convenient to obtain, greatly reduces the risk of delaying the experiment or operation time, and can be applied to the field preparation in the experiment or surgical operation. The hydrogel obtained by the preparation method of the present invention can be smoothly passed through a catheter and a needle when the hydrogel is passed through a longer catheter and injected from a smaller needle of, for example, 30G or less, and in particular, in practical applications, can be used for various specific delivery systems such as in situ implantation in biomedicine, tissue filling, embolization surgery, anti-adhesion therapy, wound treatment, preparation of ex vivo or in vivo tissue constructs, diabetes therapy, coating of implant devices, and the like.

Compared with the prior art, in the application method of the hydrogel, the hydrogel is obtained by the crosslinking reaction of the suspension of the alkaline earth metal salt and the alginate aqueous solution, so that the hydrogel has good injectability and tissue retentivity, can obtain the satisfactory injectable hydrogel in a short time, meets the requirement of organism injection, and has a wide application range.

As shown in FIG. 2, the hydrogel of the present invention and its production method will be further described with reference to specific examples. Since the injectability and tissue retention are related to the storage modulus of the hydrogel, the section mainly records the change of the storage modulus of the hydrogel.

Example 1

Setting the preparation temperature to 0-25 deg.C

Determining that the alginate component is an aqueous solution of sodium alginate and mannitol, the alkaline earth metal salt component is calcium citrate, and the aqueous solution component is water and mannitol.

Step (2), preparing the sodium alginate component: 2g of mannitol and 3g of sodium alginate were dissolved in 100g of water and stirred until all the mannitol and the sodium alginate were dissolved.

Step (3), preparation of aqueous solution components: 3.8g of mannitol were dissolved in 100g of water.

Step (4), sample loading: a first syringe, with a maximum mark of 3 ml, was taken and connected to a three-way valve. The plunger of the first syringe is removed and the three-way valve is closed. 0.021 g of calcium citrate is loaded into the first syringe, the three-way valve is opened to connect the air and the plunger is placed back into the first syringe, after the air in the first syringe is expelled, only calcium citrate powder remains, and the three-way valve is closed. A second syringe was used to take 0.5 ml of the aqueous solution and the front end was purged of air and connected to a three-way valve. A third syringe was used to draw in 1 ml of the sodium alginate composition, and the three-way valve was connected after the air in the syringe was expelled.

Step (5), preparing hydrogel: communicating the two injectors filled with the aqueous solution and the calcium citrate powder, pushing the aqueous solution into the injector filled with the calcium citrate powder and closing the three-way valve. The mixture was shaken and mixed for 5 minutes to give a milky white suspension containing 30% calcium citrate dissolved therein. And opening the three-way valve within 12 hours to push the suspension into the syringe filled with the sodium alginate aqueous solution, so that the suspension is uniformly mixed.

And (6) testing the storage modulus of the hydrogel.

In this embodiment, a uniformly mixed hydrogel is finally obtained, and the test result shows that after the suspension is pushed into an injector filled with an aqueous solution of sodium alginate, the hydrogel reaches a storage modulus of 4000Gpa in 1 minute, the storage modulus is moderate, the storage modulus is about 80% of the final storage modulus, when the hydrogel is injected from a needle below 30G through a long catheter, the needle is not blocked, and the retention in tissues is excellent. The change in storage modulus of the hydrogel is shown in the graph of FIG. 2.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. The hydrogel for injecting organisms is characterized in that the hydrogel is formed by mixing and crosslinking alkaline earth metal salt, an aqueous solution containing auxiliary materials and an alginate aqueous solution in a constant temperature environment, and the storage modulus of the hydrogel is 60% -85% of the final storage modulus of the hydrogel;

the alkaline earth metal salt is alkaline earth metal salt containing magnesium, calcium, strontium and barium, and the form of the alkaline earth metal salt is at least one of sulfate, citrate, gluconate, lactate, carbonate, phosphate and alginate.

2. The hydrogel according to claim 1, wherein the mixing time of the alkaline earth metal salt and the aqueous solution containing the auxiliary material is 1 hour or less.

3. The hydrogel according to claim 1, wherein the mixing temperature of the alkaline earth metal salt and the aqueous solution containing the supplementary material is 0 to 25 ℃.

4. The hydrogel for infusing into a biological subject of claim 1, wherein said hydrogel prior to infusion into a biological subject has a storage modulus of from 60% to 85% of the maximum storage modulus of the hydrogel.

5. The hydrogel for infusing into a living organism of claim 1, wherein the hydrogel has a storage modulus of 2880 to 4250Gpa prior to infusing into a living organism.

6. A hydrogel for injecting a biological body as defined in claim 1, which is prepared by a method comprising:

mixing water and auxiliary materials to form an aqueous solution;

mixing alkaline earth metal salt with the aqueous solution to form a mixed solution, and dissolving 30-50% of the alkaline earth metal salt in the aqueous solution; the alkaline earth metal salt is alkaline earth metal salt containing magnesium, calcium, strontium and barium, and the form of the alkaline earth metal salt is at least one of sulfate, citrate, gluconate, lactate, carbonate, phosphate and alginate;

uniformly mixing the mixed solution and an alginate aqueous solution under a constant temperature environment to form hydrogel;

wherein, the alginate and the alkaline earth metal salt are different salts.

7. The hydrogel for infusing into a biological subject of claim 6, wherein said mixed solution is mixed with an aqueous alginate solution for a time period of 5 minutes or less.

8. The hydrogel for injecting living organisms according to claim 7, wherein the mixed solution is mixed with the alginate solution by means of manual or mechanical vibration.

9. The hydrogel for infusing into a biological subject of claim 8, wherein said mixed solution and aqueous alginate solution form a maximum hydrogel storage modulus within 1 minute of mixing that is between 60% and 85% of the final storage modulus of the hydrogel.

10. The hydrogel for injecting into a living body according to claim 8, wherein the maximum value of the hydrogel storage modulus formed by mixing the mixed solution with the alginate aqueous solution within 1 minute is 2880-4250 GPa.

11. Use of a hydrogel according to any one of claims 1 to 10 for the treatment of heart failure.