CN114805856B - An injectable pH/ROS dual-responsive hydrogel and its preparation method and application - Google Patents
An injectable pH/ROS dual-responsive hydrogel and its preparation method and application Download PDFInfo
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- CN114805856B CN114805856B CN202210493702.2A CN202210493702A CN114805856B CN 114805856 B CN114805856 B CN 114805856B CN 202210493702 A CN202210493702 A CN 202210493702A CN 114805856 B CN114805856 B CN 114805856B
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- hyaluronic acid
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 34
- 230000009977 dual effect Effects 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims abstract description 143
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 79
- -1 aldehyde group modified hyaluronic acid Chemical class 0.000 claims abstract description 67
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 229920002674 hyaluronan Polymers 0.000 claims description 48
- 229960003160 hyaluronic acid Drugs 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000004108 freeze drying Methods 0.000 claims description 24
- 125000003172 aldehyde group Chemical group 0.000 claims description 21
- 150000002009 diols Chemical class 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 17
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- 230000035484 reaction time Effects 0.000 claims description 15
- 239000000178 monomer Substances 0.000 claims description 14
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 12
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003456 ion exchange resin Substances 0.000 claims description 12
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 12
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 12
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 12
- DGORTXQWDDXSIQ-UHFFFAOYSA-N 5-borono-2-fluorobenzoic acid Chemical compound OB(O)C1=CC=C(F)C(C(O)=O)=C1 DGORTXQWDDXSIQ-UHFFFAOYSA-N 0.000 claims description 10
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 7
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 6
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 6
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 6
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 6
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 6
- UZUMQQZPGOFJBQ-UHFFFAOYSA-N 1-aminopropane-1,2-diol Chemical compound CC(O)C(N)O UZUMQQZPGOFJBQ-UHFFFAOYSA-N 0.000 claims description 3
- KWNPRVWFJOSGMZ-UHFFFAOYSA-N 2-boronobenzoic acid Chemical class OB(O)C1=CC=CC=C1C(O)=O KWNPRVWFJOSGMZ-UHFFFAOYSA-N 0.000 claims description 3
- ARZSRJNMSIMAKS-UHFFFAOYSA-N 4-aminobutane-1,2-diol Chemical compound NCCC(O)CO ARZSRJNMSIMAKS-UHFFFAOYSA-N 0.000 claims description 3
- CZDWJVSOQOMYGC-UHFFFAOYSA-N 4-borono-2-fluorobenzoic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C(F)=C1 CZDWJVSOQOMYGC-UHFFFAOYSA-N 0.000 claims description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 3
- 235000011037 adipic acid Nutrition 0.000 claims description 3
- 239000001361 adipic acid Substances 0.000 claims description 3
- 239000000499 gel Substances 0.000 abstract description 12
- 230000007935 neutral effect Effects 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 41
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 13
- 239000002953 phosphate buffered saline Substances 0.000 description 13
- 238000000502 dialysis Methods 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—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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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
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- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
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Abstract
The invention provides injectable pH/ROS dual-response hydrogel, a preparation method and application thereof, wherein phenylboronic acid and aldehyde group modified hyaluronic acid PBS solution and glycol and hydrazide modified hyaluronic acid PBS solution are utilized for mixing reaction, and the injectable pH/ROS dual-response hydrogel is obtained. The hydrogel prepared by the method has simple preparation method, injectability, mechanical property and gel forming time which can be changed according to the needs; in addition, the system can form gel under neutral condition, is suitable for wrapping active factors, cells and medicines, and can be applied to the field of tissue engineering.
Description
Technical Field
The invention relates to the technical field of hydrogels, in particular to an injectable pH/ROS dual-response hydrogel, a preparation method and application thereof.
Background
The hydrogel has a 3D polymer network structure with certain mechanical properties and similar extracellular matrix and viscoelasticity, can be used for diffusing and exchanging nutrient substances, gases and the like with the surrounding environment, and can also be used as a controllable delivery system of cells, drug molecules and growth factors. The injectable hydrogels, due to their shear thinning properties, can be injected directly into the target site via a syringe or microcatheter. Recently, ROS-responsive injectable hydrogels have also attracted increasing attention due to their adaptive ability to handle harsh microenvironments. In order to allow ROS response, a reversible covalent cross-linked network must be formed in the hydrogel. Boric acid and its derivatives can reversibly bind to cis-diols and respond to changes in microenvironment (glucose, pH and ROS). However, the hydrogel formed by the natural polymer modified by phenylboronic acid at present often needs a higher pH value, which severely limits the application of the hydrogel in vivo. By decreasing the pKa of phenylboronic acid, a gel can be formed under neutral conditions. Therefore, the device can carry cells, drug molecules, growth factors and the like to be delivered to damaged parts so as to realize accurate release of drugs, cells and the like.
Disclosure of Invention
The invention overcomes the defects in the prior art and provides an injectable pH/ROS dual-response hydrogel, a preparation method and application thereof, wherein the injectable pH/ROS dual-response hydrogel formed under neutral conditions is prepared by mixing a diol-and-hydrazide-modified hyaluronic acid monomer, phenylboronic acid and an aldehyde-modified hyaluronic acid monomer, and then Schiff base reaction and boric acid ester reaction, and the injectable hydrogel with different mechanical properties and gel forming time can be obtained by the proportion of the two components.
The aim of the invention is achieved by the following technical scheme.
An injectable pH/ROS dual response hydrogel and a preparation method thereof are carried out according to the following steps:
Step 1, preparation of phenylboronic acid and aldehyde group modified hyaluronic acid:
Dissolving hyaluronic acid in water, adding ion exchange resin, stirring for 5-36h, filtering, regulating filtrate to neutrality by tetrabutylammonium hydroxide, freeze-drying to obtain oil-soluble hyaluronic acid, dissolving the oil-soluble hyaluronic acid in dimethyl sulfoxide, adding 1, 3-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and carboxyphenylboronic acid derivatives into the oil-soluble hyaluronic acid, heating to 25-75 ℃ to react for 10-36h to obtain phenylboronic acid modified hyaluronic acid solution, dialyzing and freeze-drying the reacted solution to obtain phenylboronic acid modified hyaluronic acid, dissolving phenylboronic acid modified hyaluronic acid in water, adding sodium periodate into the phenylboronic acid modified hyaluronic acid, performing light-shielding reaction for 1-10h, adding glycol, dialyzing and freeze-drying to obtain phenylboronic acid modified hyaluronic acid, wherein the mass ratio of the sodium hyaluronate to the ion exchange resin is 1:0.1-1:10, the phenylboronic acid derivative adopts 3-carboxyl-4-fluorobenzeneboronic acid, 4-carboxyl-3-fluorobenzeneboronic acid, 5-carboxyl-2-phenylboronic acid, the mole ratio of the phenylboronic acid to the phenylboronic acid modified hyaluronic acid is 1:1:1-10, and the mole ratio of phenylboronic acid to the phenylboronic acid modified hyaluronic acid to the phenylboronic acid is 1:1-5-2, and the mole ratio of phenylboronic acid to the phenylboronic acid modified hyaluronic acid to 1:1:1-10:1.5-5-6, and the mole ratio of phenylboronic acid to 1-2-carboxyl-1-1:10 to the phenylboronic acid is 1-1:1;
As shown in fig. 1, the preparation flow of phenylboronic acid and aldehyde group modified hyaluronic acid is schematically shown.
Step 2, preparation of diol and hydrazide modified hyaluronic acid:
dissolving hyaluronic acid into water, adding a catalyst to activate carboxyl, reacting for 2-12h, adding aminopropanediol and dihydrazide, heating to 20-37 ℃ to react for 10-36h, dialyzing, and freeze-drying to obtain the hyaluronic acid modified by glycol and dihydrazide, wherein the catalyst adopts 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, the molar ratio of the catalyst to carboxyl in the hyaluronic acid is 1:1-10:1, the amino propanediol and dihydrazide are sequentially added after the amino diol is added to react for a period of time, the dihydrazide is added after the dihydrazide is added to react for a period of time, the amino diol is added or simultaneously, the amino diol adopts 3-amino-1, 2-propanediol, 4-amino-1, 2-butanediol, beta-D-ribopyranosamine or D-ribopyranosamine, the dihydrazide is adopted, the molar ratio of the adipic acid to the carboxyl in the hyaluronic acid is 1:1:10:1, and the dihydrazide is added after the dihydrazide is added to react for a period of time, and the amino diol is added to react for a period of time;
as shown in fig. 2, a schematic of the diol and hydrazide modified hyaluronic acid preparation scheme.
And 3, dissolving the phenylboronic acid and the aldehyde group modified hyaluronic acid prepared in the step 1 in a PBS solution to obtain a phenylboronic acid and aldehyde group modified hyaluronic acid PBS solution with the mass fraction of 3-20%, dissolving the diol and the hydrazide modified hyaluronic acid prepared in the step 2 in the PBS solution to obtain a diol and hydrazide modified hyaluronic acid PBS solution with the mass fraction of 1-10%, and mixing the two solutions for 5-120 seconds to obtain the injectable pH/ROS dual-response hydrogel, wherein the proportions of the hydrazide, the aldehyde group, the phenylboronic acid and the diol are all 0.5-5.
In the step1, the mass ratio of the sodium hyaluronate to the ion exchange resin is 1:1, the stirring reaction time is 24 hours, the phenylboronic acid derivative adopts 3-carboxyl-4-fluorobenzeneboronic acid, the heating temperature is 45 ℃, and the reaction time is 24 hours.
In the step 2, the catalyst adopts 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, the reaction time of hyaluronic acid and the catalyst is 48 hours, the amino propylene glycol and the dihydrazide are added simultaneously in the sequence of adding the dihydrazide and the amino glycol, the amino glycol adopts 3-amino-1, 2-propanediol, the dihydrazide adopts carbonic dihydrazide, and the heating reaction time is 24 hours.
In the step 3, the mass fraction of the hyaluronic acid monomer modified by aldehyde groups and phenylboronic acid is 5-12%, and the mass fraction of the hyaluronic acid monomer modified by glycol and hydrazide is 2-7%.
In step 3, the ratio of hydrazide to aldehyde groups, phenylboronic acid to diol in both solutions is 1-5.
The beneficial effects of the invention are as follows: the hydrogel prepared by the method has simple preparation method, injectability, mechanical property and gel forming time which can be changed according to the needs; in addition, the system can form gel under neutral condition, is suitable for wrapping active factors, cells and medicines, and can be applied to the field of tissue engineering.
Drawings
FIG. 1 is a schematic diagram of a preparation scheme for preparing phenylboronic acid and aldehyde group modified hyaluronic acid monomers according to the present invention;
FIG. 2 is a schematic diagram of a preparation scheme for preparing diol and hydrazide-modified hyaluronic acid monomers according to the present invention;
FIG. 3 is a nuclear magnetic spectrum of the preparation of phenylboronic acid and aldehyde group modified hyaluronic acid monomers according to the present invention;
FIG. 4 is a nuclear magnetic spectrum of the preparation of diol and hydrazide modified hyaluronic acid monomers in accordance with the present invention;
FIG. 5 is the gel formation time of a dual response hydrogel prepared in accordance with the present invention;
fig. 6 is a graph of the rheological properties of dual response hydrogels prepared according to the present invention.
Detailed Description
The technical scheme of the invention is further described by specific examples.
Example 1
Step 1, 1g of hyaluronic acid, 1.37g of carbonic dihydrazide, 1.48g of 3-amino-1, 2-propanediol, 1.29g of 1-hydroxybenzotriazole and 1.16g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are weighed by a balance, and a proper amount of water is put into a single-neck flask, heated at 25 ℃ to start reaction, and the reaction time is 48 hours.
And 2, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain the diol-and-hydrazide-modified hyaluronic acid.
And 3, weighing 1g of hyaluronic acid, 1g of ion exchange resin and a proper amount of water by using a balance, adding into a single-mouth bottle, stirring for 24 hours, filtering after the reaction is finished, regulating the filtrate to be neutral by using tetrabutylammonium hydroxide, and freeze-drying to obtain the oil-soluble hyaluronic acid.
And 4, weighing 1g of oil-soluble hyaluronic acid, 0.6g of N, N' -dicyclohexylcarbodiimide, 0.5g of 3-carboxyl-4-fluorobenzeneboronic acid, 0.5g of 4-dimethylaminopyridine and a proper amount of dimethyl sulfoxide by using a balance, adding into a single-mouth bottle, heating to 45 ℃ and starting to react for 24 hours.
And 5, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain phenylboronic acid modified hyaluronic acid.
And 6, weighing 1g of phenylboronic acid modified hyaluronic acid, 0.5g of sodium periodate and a proper amount of water by using a balance, adding into a single-port bottle, heating to 25 ℃ to start reaction, and reacting for 5 hours.
And 7, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain the hyaluronic acid modified by aldehyde groups and phenylboronic acid.
And 8, dissolving the prepared glycol and hydrazide modified hyaluronic acid in PBS (phosphate buffered saline) solution by using a balance to prepare a solution with a certain mass fraction. The mass fraction is 1.3%.
And 9, dissolving the prepared aldehyde group and phenylboronic acid modified hyaluronic acid in PBS (phosphate buffer solution) by using a balance to prepare a solution with a certain mass fraction. The mass fraction is 2.6%. Then 200. Mu.L of the diol-and hydrazide-modified hyaluronic acid solution and 200. Mu.L of the aldehyde-and phenylboronic acid-modified hyaluronic acid solution were mixed to form a gel.
Example 2
Step 1, 1g of hyaluronic acid, 1.37g of carbonic dihydrazide, 1.48g of 3-amino-1, 2-propanediol, 1.29g of 1-hydroxybenzotriazole and 1.16g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are weighed by a balance, and a proper amount of water is put into a single-neck flask, heated at 25 ℃ to start reaction, and the reaction time is 48 hours.
And 2, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain the diol-and-hydrazide-modified hyaluronic acid.
And 3, weighing 1g of hyaluronic acid, 1g of ion exchange resin and a proper amount of water by using a balance, adding into a single-mouth bottle, stirring for 24 hours, filtering after the reaction is finished, regulating the filtrate to be neutral by using tetrabutylammonium hydroxide, and freeze-drying to obtain the oil-soluble hyaluronic acid.
And 4, weighing 1g of oil-soluble hyaluronic acid, 0.6g of N, N' -dicyclohexylcarbodiimide, 0.5g of 3-carboxyl-4-fluorobenzeneboronic acid, 0.5g of 4-dimethylaminopyridine and a proper amount of dimethyl sulfoxide by using a balance, adding into a single-mouth bottle, heating to 45 ℃ and starting to react for 24 hours.
And 5, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain phenylboronic acid modified hyaluronic acid.
And 6, weighing 1g of phenylboronic acid modified hyaluronic acid, 0.5g of sodium periodate and a proper amount of water by using a balance, adding into a single-port bottle, heating to 25 ℃ to start reaction, and reacting for 5 hours.
And 7, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain the hyaluronic acid modified by aldehyde groups and phenylboronic acid.
And 8, dissolving the prepared glycol and hydrazide modified hyaluronic acid in PBS (phosphate buffered saline) solution by using a balance to prepare a solution with a certain mass fraction. The mass fraction is 2%.
And 9, dissolving the prepared aldehyde group and phenylboronic acid modified hyaluronic acid in PBS (phosphate buffer solution) by using a balance to prepare a solution with a certain mass fraction. The mass fraction is 4%. Then 200. Mu.L of the diol-and hydrazide-modified hyaluronic acid solution and 200. Mu.L of the aldehyde-and phenylboronic acid-modified hyaluronic acid solution were mixed to form a gel.
Example 3
Step 1, 1g of hyaluronic acid, 1.37g of carbonic dihydrazide, 1.48g of 3-amino-1, 2-propanediol, 1.29g of 1-hydroxybenzotriazole and 1.16g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are weighed by a balance, and a proper amount of water is put into a single-neck flask, heated at 25 ℃ to start reaction, and the reaction time is 48 hours.
And 2, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain the diol-and-hydrazide-modified hyaluronic acid.
And 3, weighing 1g of hyaluronic acid, 1g of ion exchange resin and a proper amount of water by using a balance, adding into a single-mouth bottle, stirring for 24 hours, filtering after the reaction is finished, regulating the filtrate to be neutral by using tetrabutylammonium hydroxide, and freeze-drying to obtain the oil-soluble hyaluronic acid.
And 4, weighing 1g of oil-soluble hyaluronic acid, 0.6g of N, N' -dicyclohexylcarbodiimide, 0.5g of 3-carboxyl-4-fluorobenzeneboronic acid, 0.5g of 4-dimethylaminopyridine and a proper amount of dimethyl sulfoxide by using a balance, adding into a single-mouth bottle, heating to 45 ℃ and starting to react for 24 hours.
And 5, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain phenylboronic acid modified hyaluronic acid.
And 6, weighing 1g of phenylboronic acid modified hyaluronic acid, 0.5g of sodium periodate and a proper amount of water by using a balance, adding into a single-port bottle, heating to 25 ℃ to start reaction, and reacting for 5 hours.
And 7, after the reaction is finished, pouring the reacted solution into a dialysis bag, dialyzing for 3 days, changing water for 3 times per day, and freeze-drying the dialyzed solution to obtain the hyaluronic acid modified by aldehyde groups and phenylboronic acid.
And 8, dissolving the prepared glycol and hydrazide modified hyaluronic acid in PBS (phosphate buffered saline) solution by using a balance to prepare a solution with a certain mass fraction. The mass fraction is 3.3%.
And 9, dissolving the prepared aldehyde group and phenylboronic acid modified hyaluronic acid in PBS (phosphate buffer solution) by using a balance to prepare a solution with a certain mass fraction. The mass fraction is 6.6%. Then 200. Mu.L of the diol-and hydrazide-modified hyaluronic acid solution and 200. Mu.L of the aldehyde-and phenylboronic acid-modified hyaluronic acid solution were mixed to form a gel.
As shown in FIG. 3, nuclear magnetic characterization is carried out on the prepared phenylboronic acid and aldehyde group modified hyaluronic acid monomer, obvious benzene ring peaks appear at 7.0-8.5ppm, which indicates that 3-carboxyl-4-fluorobenzeneboronic acid has successfully reacted with hydroxyl on hyaluronic acid, which proves that 3-carboxyl-4-fluorobenzeneboronic acid modified hyaluronic acid has successfully synthesized, aldehyde group modification is qualitatively carried out and the content thereof is quantified through the reaction of aldehyde group and phenylboronic acid modified hyaluronic acid with tert-butyl hydrazinoformate, obvious tert-butyl peaks appear at 1.25-1.5ppm, which indicates that successful synthesis of aldehyde group and phenylboronic acid modified hyaluronic acid is shown, and the substitution degrees of phenylboronic acid and aldehyde group can be calculated to be 10% and 9.5% respectively through integration.
As shown in fig. 4, nuclear magnetic characterization of the prepared diol and hydrazide modified hyaluronic acid monomer showed that an obvious-CH-peak appeared at 2.5-3.0ppm, indicating successful synthesis of diol modified hyaluronic acid, and for successful modification of qualitative and quantitative hydrazides, using diol and hydrazide modified hyaluronic acid reacted with benzaldehyde, an obvious benzene ring peak appeared at 7.0-8.0ppm, indicating successful modification of hydrazides, and the degree of substitution of diol and hydrazides was 15% and 17.2%, respectively, as calculated by integration.
As shown in fig. 5, the prepared hydrazide and diol modified hyaluronic acid and aldehyde and phenylboronic acid modified hyaluronic acid were subjected to a gel forming time test in which the gel forming time was gradually reduced as the polymer concentration was increased.
As shown in fig. 6, the prepared hydrazide and diol modified hyaluronic acid and aldehyde group and phenylboronic acid modified hyaluronic acid were subjected to rheological property test by regulating and controlling the concentrations of the two components. The results of time scanning and frequency scanning show that the storage modulus and the loss modulus of the hydrogel are increased to a certain extent along with the increase of the concentration of the polymer, and the mechanical strength of the hydrogel is adjustable to be 10-2000Pa.
The foregoing has described exemplary embodiments of the invention, it being understood that any simple variations, modifications, or other equivalent arrangements which would not unduly obscure the invention may be made by those skilled in the art without departing from the spirit of the invention.
Claims (9)
1. An injectable pH/ROS dual-responsive hydrogel, characterized by: the method comprises the following steps of:
Step 1, preparation of phenylboronic acid and aldehyde group modified hyaluronic acid:
Dissolving hyaluronic acid in water, adding ion exchange resin, stirring for 5-36h, filtering, regulating filtrate to neutrality by tetrabutylammonium hydroxide, freeze-drying to obtain oil-soluble hyaluronic acid, dissolving the oil-soluble hyaluronic acid in dimethyl sulfoxide, adding 1, 3-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and carboxyphenylboronic acid derivatives into the oil-soluble hyaluronic acid, heating to 25-75 ℃ to react for 10-36h to obtain phenylboronic acid modified hyaluronic acid solution, dialyzing and freeze-drying the reacted solution to obtain phenylboronic acid modified hyaluronic acid, dissolving phenylboronic acid modified hyaluronic acid in water, adding sodium periodate into the phenylboronic acid modified hyaluronic acid, performing light-shielding reaction for 1-10h, adding glycol, dialyzing and freeze-drying to obtain phenylboronic acid modified hyaluronic acid, wherein the mass ratio of the sodium hyaluronate to the ion exchange resin is 1:0.1-1:10, the phenylboronic acid derivative adopts 3-carboxyl-4-fluorobenzeneboronic acid, 4-carboxyl-3-fluorobenzeneboronic acid, 5-carboxyl-2-phenylboronic acid, the mole ratio of the phenylboronic acid to the phenylboronic acid is 1:1-10, and the phenylboronic acid modified hyaluronic acid is 1:1-5-2, the mole ratio of phenylboronic acid to the phenylboronic acid modified hyaluronic acid is 1:1-10, and the mole ratio of phenylboronic acid to the phenylboronic acid modified hyaluronic acid is 1:1-5:1-5-2, and the phenylboronic acid is 1:1-10, the mole ratio of the phenylboronic acid to 1-1:1-2-1:10, and the phenylboronic acid is obtained.
Step 2, preparation of diol and hydrazide modified hyaluronic acid:
Dissolving hyaluronic acid into water, adding a catalyst to activate carboxyl, reacting for 2-12h, adding aminopropanediol and dihydrazide, heating to 20-37 ℃ to react for 10-36h, dialyzing, and freeze-drying to obtain the hyaluronic acid modified by glycol and dihydrazide, wherein the catalyst adopts 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, the molar ratio of the catalyst to carboxyl in the hyaluronic acid is 1:1-10:1, the amino propanediol and dihydrazide are sequentially added after the amino diol is added to react for a period of time, the dihydrazide is added after the dihydrazide is added to react for a period of time, the amino diol is added or simultaneously, the amino diol adopts 3-amino-1, 2-propanediol, 4-amino-1, 2-butanediol, beta-D-ribopyranosamine or D-ribopyranosamine, and the dihydrazide is adopted, the molar ratio of the adipic acid to the carboxyl in the hyaluronic acid is 1:1:10:1, and the dihydrazide is added after the dihydrazide is reacted for a period of time, and the amino diol is added to react for a period of time;
And 3, dissolving the phenylboronic acid and the aldehyde group modified hyaluronic acid prepared in the step 1 in a PBS solution to obtain a phenylboronic acid and aldehyde group modified hyaluronic acid PBS solution with the mass fraction of 3-20%, dissolving the diol and the hydrazide modified hyaluronic acid prepared in the step 2 in the PBS solution to obtain a diol and hydrazide modified hyaluronic acid PBS solution with the mass fraction of 1-10%, and mixing the two solutions for 5-120 seconds to obtain the injectable pH/ROS dual-response hydrogel, wherein the mass ratio of the hydrazide to the aldehyde group to the phenylboronic acid to the diol is 0.5-5.
2. The injectable pH/ROS dual-responsive hydrogel of claim 1, wherein: in the step 1, the mass ratio of the sodium hyaluronate to the ion exchange resin is 1:1, the stirring reaction time is 24 hours, the phenylboronic acid derivative adopts 3-carboxyl-4-fluorobenzeneboronic acid, the heating temperature is 45 ℃, and the reaction time is 24 hours.
3. The injectable pH/ROS dual-responsive hydrogel of claim 1, wherein: in the step 2, the catalyst adopts 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, the reaction time of hyaluronic acid and the catalyst is 48 hours, the amino propylene glycol and the dihydrazide are added simultaneously in the sequence of adding the dihydrazide and the amino glycol, the amino glycol adopts 3-amino-1, 2-propanediol, the dihydrazide adopts carbonic dihydrazide, and the heating reaction time is 24 hours.
4. The injectable pH/ROS dual-responsive hydrogel of claim 1, wherein: in the step 3, the mass fraction of the hyaluronic acid monomer modified by aldehyde groups and phenylboronic acid is 5-12%, the mass fraction of the hyaluronic acid monomer modified by glycol and hydrazide is 2-7%, and the mass ratio of the hydrazide to aldehyde groups to phenylboronic acid to glycol in the two solutions is 1-5.
5. A method of preparing an injectable pH/ROS dual-response hydrogel according to any one of claims 1-4, wherein: the method comprises the following steps of:
Step 1, preparation of phenylboronic acid and aldehyde group modified hyaluronic acid:
Dissolving hyaluronic acid in water, adding ion exchange resin, stirring for 5-36h, filtering, regulating filtrate to neutrality by tetrabutylammonium hydroxide, freeze-drying to obtain oil-soluble hyaluronic acid, dissolving the oil-soluble hyaluronic acid in dimethyl sulfoxide, adding 1, 3-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and carboxyphenylboronic acid derivatives into the oil-soluble hyaluronic acid, heating to 25-75 ℃ to react for 10-36h to obtain phenylboronic acid modified hyaluronic acid solution, dialyzing and freeze-drying the reacted solution to obtain phenylboronic acid modified hyaluronic acid, dissolving phenylboronic acid modified hyaluronic acid in water, adding sodium periodate into the phenylboronic acid modified hyaluronic acid, performing light-shielding reaction for 1-10h, adding glycol, dialyzing and freeze-drying to obtain phenylboronic acid modified hyaluronic acid, wherein the mass ratio of the sodium hyaluronate to the ion exchange resin is 1:0.1-1:10, the phenylboronic acid derivative adopts 3-carboxyl-4-fluorobenzeneboronic acid, 4-carboxyl-3-fluorobenzeneboronic acid, 5-carboxyl-2-phenylboronic acid, the mole ratio of the phenylboronic acid to the phenylboronic acid is 1:1-10, and the phenylboronic acid modified hyaluronic acid is 1:1-5-2, the mole ratio of phenylboronic acid to the phenylboronic acid modified hyaluronic acid is 1:1-10, and the mole ratio of phenylboronic acid to the phenylboronic acid modified hyaluronic acid is 1:1-5:1-5-2, and the phenylboronic acid is 1:1-10, the mole ratio of the phenylboronic acid to 1-1:1-2-1:10, and the phenylboronic acid is obtained.
Step 2, preparation of diol and hydrazide modified hyaluronic acid:
Dissolving hyaluronic acid into water, adding a catalyst to activate carboxyl, reacting for 2-12h, adding aminopropanediol and dihydrazide, reacting for 10-36h at 20-37 ℃, dialyzing, and freeze-drying to obtain glycol-and-hydrazide-modified hyaluronic acid, wherein the catalyst adopts 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, the molar ratio of carboxyl in the catalyst to the hyaluronic acid is 1:1-10:1, the amino propanediol and dihydrazide are added in the order of adding the amino diol to react for a period of time, then adding the dihydrazide to react for a period of time, and then adding the amino diol to react with the amino diol, wherein the amino diol adopts 3-amino-1, 2-propanediol, 4-amino-1, 2-butanediol, beta-D-ribopyranosamine or D-ribofuranamine, and the dihydrazide is adopted, the molar ratio of carboxyl in the adipic acid to the hyaluronic acid is 1:1:10:1, and the dihydrazide is adopted, and the dihydrazide is added to react for a period of time, and the dihydrazide is added to the dihydrazide to react for a period of time;
And 3, dissolving the phenylboronic acid and the aldehyde group modified hyaluronic acid prepared in the step 1 in a PBS solution to obtain a phenylboronic acid and aldehyde group modified hyaluronic acid PBS solution with the mass fraction of 3-20%, dissolving the diol and the hydrazide modified hyaluronic acid prepared in the step 2 in the PBS solution to obtain a diol and hydrazide modified hyaluronic acid PBS solution with the mass fraction of 1-10%, and mixing the two solutions for 5-120 seconds to obtain the injectable pH/ROS dual-response hydrogel, wherein the mass ratio of the hydrazide to the aldehyde group to the phenylboronic acid to the diol is 0.5-5.
6. The method for preparing the injectable pH/ROS dual response hydrogel of claim 5, wherein the method comprises the steps of: in the step 1, the mass ratio of the sodium hyaluronate to the ion exchange resin is 1:1, the stirring reaction time is 24 hours, the phenylboronic acid derivative adopts 3-carboxyl-4-fluorobenzeneboronic acid, the heating temperature is 45 ℃, and the reaction time is 24 hours.
7. The method for preparing the injectable pH/ROS dual response hydrogel of claim 5, wherein the method comprises the steps of: in the step 2, the catalyst adopts 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, the reaction time of hyaluronic acid and the catalyst is 48 hours, the amino propylene glycol and the dihydrazide are added simultaneously in the sequence of adding the dihydrazide and the amino glycol, the amino glycol adopts 3-amino-1, 2-propanediol, the dihydrazide adopts carbonic dihydrazide, and the heating reaction time is 24 hours.
8. The method for preparing the injectable pH/ROS dual response hydrogel of claim 5, wherein the method comprises the steps of: in the step3, the mass fraction of the hyaluronic acid monomer modified by aldehyde groups and phenylboronic acid is 5-12%, and the mass fraction of the hyaluronic acid monomer modified by glycol and hydrazide is 2-7%.
9. The method for preparing the injectable pH/ROS dual response hydrogel of claim 5, wherein the method comprises the steps of: in the step 3, the mass ratio of the hydrazide to the aldehyde group to the phenylboronic acid to the diol in the two solutions is 1-5.
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