CN113209375A - Preparation method and application of hydrogel based on arylborate crosslinking and having self-repairing and injectable properties - Google Patents
Preparation method and application of hydrogel based on arylborate crosslinking and having self-repairing and injectable properties Download PDFInfo
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- CN113209375A CN113209375A CN202110429117.1A CN202110429117A CN113209375A CN 113209375 A CN113209375 A CN 113209375A CN 202110429117 A CN202110429117 A CN 202110429117A CN 113209375 A CN113209375 A CN 113209375A
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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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
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- 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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- 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
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- 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
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
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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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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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
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/04—Alginic acid; Derivatives thereof
Abstract
A preparation method and application of hydrogel with self-repairing and injectable performances based on aryl borate crosslinking are disclosed, wherein Alg-BOB is synthesized by a one-step method, and three-dimensional network-shaped hydrogel is constructed by single-component self-crosslinking. The invention solves the technical defect that the conventional phenylboronic acid with high pKa value can not construct hydrogel used under physiological condition pH value, and is based on the principle that the phenylboronic acid half-ester group on the side chain of Alg-BOB and the vicinal diol group on the sugar ring chain of sodium alginate form a reversible arylboronic acid ester dynamic bond under proper pH value, so that the multifunctional hydrogel with injectability and self-repairing performance can be constructed by a simple mode of adjusting pH, and the synthesis is simple and convenient, the raw materials are simple, and the gelling mode is simple. Is suitable for industrial production and has wide application scenes.
Description
Technical Field
The invention particularly relates to the technical field of preparation of high polymer materials and biomedical hydrogel, and particularly relates to a preparation method and application of hydrogel with self-repairing and injectable performances based on aryl borate crosslinking.
Background
Hydrogels are materials having a three-dimensional network structure formed by physical or chemical crosslinking of hydrophilic polymers. The hydrogel material has good biocompatibility and ion transmission capacity, the three-dimensional structure of the hydrogel material is similar to that of extracellular matrix, and the hydrogel material is convenient to design and modify, so that the hydrogel material becomes one of the most promising materials in the field of biomedical science. However, the traditional polymer hydrogel is difficult to repair once being implanted into the human body, which not only shortens the service life of the material, but also increases the risk of patients. Compared with the traditional hydrogel, the hydrogel crosslinked through the reversible dynamic bond has the injectable and self-repairing performance, can be conveniently implanted into a body in a minimally invasive mode through an injector, can realize self-repairing through the reversibility of the dynamic bond under the condition of being damaged by external force, and is expected to remarkably improve the service performance. Among these, phenylboronic acid esters formed by the reaction between phenylboronic acid and vicinal diols are one of the more common dynamic covalent bonds. However, most phenylboronic acids have relatively high pKa values (> 7.4, typically between 8 and 9), and the formation of phenylboronic acid esters is pH dependent, i.e., phenylboronic acid esters can be formed at a solution pH above their pKa value. Thus, the high pKa values of conventional phenylboronates severely impact their biomedical applications. The phenylboronic acid half-ester is a phenylboronic acid derivative which has a low pKa value (-7.2), so that the phenylboronic acid half-ester can react with vicinal diol under a physiological pH value to form an arylboronic acid ester dynamic bond, and a hydrogel capable of being used under a physiological condition is constructed.
The traditional hydrogel preparation method is complex, more than two components are needed, a chemical cross-linking agent is used, and monomers, cross-linking agents and the like with biotoxicity are remained in the system, so that the application of the monomers, the cross-linking agents and the like in the biomedical field is limited. Therefore, the simple single-component self-crosslinking and self-repairing hydrogel has great practical significance.
Sodium alginate is a natural polysaccharide which is low in price, wide in source, sustainable, biodegradable and good in biocompatibility, and the hydrogel based on sodium alginate has a huge application prospect in the biomedical field. The vicinal diol structure exists on the sugar ring of the main chain of the sodium alginate, and the preparation of dynamic hydrogels by the sodium alginate and the conventional phenylboronic acid is reported individually at present, but as mentioned above, the hydrogels are often prepared under the alkaline condition and are not suitable for most biomedical fields. Therefore, it is very necessary to design a sodium alginate hydrogel which has a single component, is simple to prepare, can be gelled under the physiological pH condition and has self-repairing and injectable properties, and the hydrogel has important significance for application in biomedical fields such as in vivo drug delivery, tissue engineering and the like.
Disclosure of Invention
In order to solve the technical defects in the prior art, the invention provides a preparation method and application of hydrogel with self-repairing and injectable performances based on aryl borate ester crosslinking, which not only retains the excellent physical and chemical properties of injectable-self-repairing hydrogel, but also ensures that the material design and synthesis process are simple and convenient, improves the biocompatibility and application value of the hydrogel, and is beneficial to further application of the hydrogel in the fields of biological medicine, tissue engineering and the like.
The technical solution adopted by the invention is as follows: a preparation method of hydrogel with self-repairing and injectable performance based on aryl borate ester crosslinking is characterized by comprising the following steps:
(1) preparing a sodium alginate solution, namely firstly weighing a certain amount of sodium alginate and dissolving the sodium alginate in deionized water to form a transparent solution A;
(2) weighing a certain amount of EDC and NHS, dissolving in deionized water, adding into the solution A prepared in the step (1), adjusting the pH of the system to 5-6, stirring and activating at room temperature to obtain an activated solution B;
(3) weighing a certain amount of 6-aminobenzo [ C ] [1,2] oxaborole-1 (3H) -alkoxide (ABOB & HCl), dissolving in a deionized water/N, N-Dimethylformamide (DMF) mixed solution, adding into the solution B prepared in the step (2), adjusting the pH of the system to be 5-6, and stirring at room temperature for reaction to obtain a solution C;
(4) dialyzing the solution C obtained in the step (3) in deionized water for several times until unreacted ABOB and catalyst in the system are completely removed, and freeze-drying the obtained solution to obtain sodium alginate Alg-BOB grafted with ABOB;
(5) and (3) preparing the self-repairing hydrogel, namely stirring and dissolving the sodium alginate Alg-BOB of the freeze-dried grafted ABOB obtained in the step (4) in deionized water, and adjusting the pH to 7.4 to obtain the multifunctional hydrogel.
The concentration of the sodium alginate solution is 0.05-0.2 g/mL.
The molar quantity ratio of the sodium alginate to the EDC and the NHS is 1 (0.5-2) to 0.1-2.
The molar quantity ratio of the sodium alginate to the ABOB is 1 (0.2-2).
And (3) in the step (2), EDC and NHS are completely dissolved in deionized water, and then the sodium alginate solution is dropwise added.
In the step (3), the ratio of deionized water/DMF is (1-2) to 1
And (3) adjusting the pH value of the system through a hydrochloric acid solution and a sodium hydroxide solution, wherein the concentrations of the hydrochloric acid solution and the sodium hydroxide solution are 0.1-1M.
In the step (5), the mass fraction of Alg-BOB is 1.5-3%.
In the step (5), the pH is adjusted by adding 10 times of PBS solution or sodium hydroxide solution.
The application of the hydrogel based on aryl borate crosslinking and having self-repairing and injectable performances in preparation of self-repairing biomedical materials is provided.
The invention has the beneficial effects that: the invention provides a preparation method and application of hydrogel with self-repairing and injectable performances based on arylborate crosslinking. The invention solves the technical defect that the conventional phenylboronic acid ester has high pKa value and cannot construct hydrogel used under physiological condition pH value, and is based on the principle that the phenylboronic acid half-ester group on the side chain of Alg-BOB and the vicinal diol group on the sugar ring chain of sodium alginate form a reversible dynamic bond under proper pH value, so that the multifunctional hydrogel with injectability and self-repairing performance can be constructed by a simple mode of adjusting the pH value, and the synthesis is simple and convenient, the raw materials are simple, and the gelling mode is simple. Is suitable for industrial production and has wide application scenes.
Drawings
FIG. 1 is a schematic diagram of the structure of a hydrogel prepared according to the present invention.
FIG. 2 shows the morphology of the hydrogel prepared by the present invention.
FIG. 3 is the NMR spectrum of Alg-BOB prepared by the present invention.
Fig. 4 is a schematic diagram of the self-healing properties of a hydrogel prepared according to the present invention, wherein fig. 4 (a) and (b) are rheological representations of hydrogel self-healing, and fig. 4 (c) is a macroscopic schematic diagram of hydrogel self-healing.
FIG. 5 is a macroscopic view of the injectability of the hydrogels prepared according to the present invention.
FIG. 6 shows the cell viability data of L929 cells cultured in the culture medium of various concentrations of Alg-BOB polymer prepared according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
An aryl boronic ester bond-based dynamic cross-linked hydrogel is prepared by catalyzing carboxyl on a sodium alginate long chain and Amino of 6-Amino-1-hydroxy-2,1-benzoxaborolane (ABOB) to form an amide bond through EDC/NHS to obtain sodium alginate Alg-BOB grafted with half phenylboronic acid ester, and forming a reversible dynamic aryl boronic ester bond between the half phenylboronic acid ester group and an ortho diol group on a sugar ring chain of the sodium alginate at a physiological pH value to obtain the injectable and self-repairing hydrogel disclosed by the invention.
The molecular structural formula of the 6-aminobenzo [ c ] [1,2] oxaborole-1 (3H) -alkoxide (ABOB & HCl) is as follows:
exemplarily, referring to the attached figure 4 of the specification, the invention discloses a macroscopic observation picture and a rheological characterization schematic diagram of the self-repairing performance of the hydrogel.
Example 1:
1) a sodium alginate solution was prepared by first weighing 1g of sodium alginate in 100mL of deionized water and stirring overnight to form a clear and homogeneous solution.
2) 0.978g of EDC and 0.299g of NHS are weighed and dissolved in deionized water, added into the solution prepared in the step 1), adjusted to pH 5-6 by hydrochloric acid solution, and stirred and activated for 1 hour at room temperature.
3) 0.473g of ABOB is weighed and dissolved in 5mL of deionized water/DMF mixed solution (1: 1), added into the solution prepared in the step 2), the pH value of the system is adjusted to 5-6 by using 0.5M hydrochloric acid solution and 0.5M sodium hydroxide solution, and the reaction is stirred for 24 hours at room temperature.
4) Dialyzing the mixture obtained in the step 3) in deionized water for several times until the unreacted ABOB, the catalyst and the like in the system are completely removed. And (4) freeze-drying the obtained solution to obtain the sodium alginate Alg-BOB grafted with the phenylboronic acid half-ester.
5) Preparation of hydrogel 20mg of Alg-BOB freeze-dried product obtained in the step 4) is dissolved in 0.75mL of deionized water by stirring, and 0.25mL of 10 times PBS solution is slowly added under stirring to obtain the target product, namely the hydrogel with injectability and self-repairing performance.
Example 2
1) A sodium alginate solution was prepared by first weighing 0.5g of sodium alginate in 50mL of deionized water and stirring overnight to form a clear and homogeneous solution.
2) 0.5g of EDC and 0.15g of NHS are weighed and dissolved in deionized water, added into the solution prepared in the step 1), adjusted to pH 5-6 by hydrochloric acid solution, and stirred and activated for 1 hour at room temperature.
3) 0.24g of ABOB was dissolved in 3mL of deionized water/DMF solution (1: 1) and added to the mixture obtained in step 2), and the pH of the system was adjusted to 5 to 6 with 0.5M hydrochloric acid solution and 0.5M sodium hydroxide solution, and the reaction was stirred at room temperature for 24 hours.
4) Dialyzing the mixture obtained in the step 3) in deionized water for several times until the unreacted ABOB, the catalyst and the like in the system are completely removed. And (4) freeze-drying the obtained solution to obtain the sodium alginate Alg-BOB grafted with the phenylboronic acid half-ester.
5) Preparation of hydrogel 20mg of Alg-BOB freeze-dried product obtained in the step 4) is dissolved in 1mL of deionized water by stirring, and 28uL of 0.5M sodium hydroxide solution is slowly added under stirring to obtain the target product, namely the hydrogel with injectability and self-repairing performance.
Example 3
1) A sodium alginate solution was prepared by first weighing 1g of sodium alginate in 50mL of deionized water and stirring overnight to form a clear and homogeneous solution.
2) Weighing 2g of EDC and 0.3g of NHS, dissolving in deionized water, adding the solution prepared in the step 1), adjusting the pH of the system to 5-6 by using hydrochloric acid solution, and stirring and activating for 1 hour at room temperature.
3) 0.473g of ABOB was weighed out and dissolved in 5mL of deionized water/DMF solution (1: 1), and added to the mixture obtained in step 2), and the system pH was adjusted to 5 to 6 with 0.5M hydrochloric acid solution and 0.5M sodium hydroxide solution, and the reaction was stirred at room temperature for 24 hours.
4) Dialyzing the mixture obtained in the step 3) in deionized water for several times until the unreacted ABOB, the catalyst and the like in the system are completely removed. And (4) freeze-drying the obtained solution to obtain the sodium alginate Alg-BOB grafted with the phenylboronic acid half-ester.
5) Preparation of hydrogel 20mg of Alg-BOB freeze-dried product obtained in the step 4) is dissolved in 0.75mL of deionized water by stirring, and 0.25mL of 10 times PBS solution is slowly added under stirring to obtain the target product, namely the hydrogel with injectability and self-repairing performance.
The skilled person should understand that: although the invention has been described in terms of the above specific embodiments, the inventive concept is not limited thereto and any modification applying the inventive concept is intended to be included within the scope of the patent claims.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (10)
1. A preparation method of hydrogel with self-repairing and injectable performance based on aryl borate ester crosslinking is characterized by comprising the following steps:
(1) preparing a sodium alginate solution, namely firstly weighing a certain amount of sodium alginate and dissolving the sodium alginate in deionized water to form a transparent solution A;
(2) weighing a certain amount of EDC and NHS, dissolving in deionized water, adding into the solution A prepared in the step (1), adjusting the pH of the system to 5-6, stirring and activating for 0.5-2 hours at room temperature to obtain an activated solution B;
(3) weighing a certain amount of 6-aminobenzo [ C ] [1,2] oxaborole-1 (3H) -alkoxide (ABOB & HCl), dissolving in a deionized water/N, N-Dimethylformamide (DMF) mixed solution, adding into the solution B prepared in the step (2), adjusting the pH of the system to be 5-6, and stirring and reacting at room temperature for 24-72 hours to obtain a solution C;
(4) dialyzing the solution C obtained in the step (3) in deionized water for several times until unreacted ABOB and catalyst in the system are completely removed, and freeze-drying the obtained solution to obtain sodium alginate (Alg-BOB) grafted with ABOB;
(5) and (3) preparing the self-repairing hydrogel, namely stirring and dissolving the freeze-dried Alg-BOB obtained in the step (4) in deionized water, and adjusting the pH to 7.4 to obtain the multifunctional hydrogel.
2. The preparation method of claim 1, wherein the concentration of the sodium alginate solution is 0.05-0.2 g/mL.
3. The method of claim 1, wherein the molar ratio of sodium alginate to EDC and NHS is 1 (0.5-2) to (0.5-2).
4. The preparation method of claim 1, wherein the molar quantity ratio of sodium alginate to ABOB is 1 (0.25-2).
5. The method according to claim 1, wherein EDC and NHS in step (2) are completely dissolved in deionized water and then the sodium alginate solution is added dropwise.
6. The preparation method according to claim 1, wherein the volume ratio of the deionized water to the DMF in the step (3) is (1-2): 1.
7. The preparation method according to claim 1, wherein the pH of the system is adjusted in the step (3) by hydrochloric acid solution and sodium hydroxide solution, and the concentration of the hydrochloric acid solution and the sodium hydroxide solution is 0.5-1M.
8. The method according to claim 1, wherein the weight fraction of Alg-BOB in step (5) is 1.5-5%.
9. The method according to claim 1, wherein the pH is adjusted by adding 10-fold PBS solution or NaOH solution in the step (5).
10. Use of an arylboronic acid ester cross-linked hydrogel with self-healing and injectable properties prepared according to the preparation method of any one of claims 1 to 9 for the preparation of self-healing biomedical materials.
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| US20150283247A1 (en) * | 2012-11-06 | 2015-10-08 | Centre National De La Recherche Scientifique (Cnrs) | Glucose responsive hydrogel comprising pba-grafted hyaluronic acid (ha) |
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| CN108421042A (en) * | 2018-04-17 | 2018-08-21 | 南京邮电大学 | A kind of preparation method of light-operated degradation hydrogel |
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