CN117777489A - Natural polysaccharide hydrogel for bone repair and preparation method and application method thereof - Google Patents
Natural polysaccharide hydrogel for bone repair and preparation method and application method thereof Download PDFInfo
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- CN117777489A CN117777489A CN202211160781.1A CN202211160781A CN117777489A CN 117777489 A CN117777489 A CN 117777489A CN 202211160781 A CN202211160781 A CN 202211160781A CN 117777489 A CN117777489 A CN 117777489A
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- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 64
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 64
- 150000004676 glycans Chemical class 0.000 title claims abstract description 63
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 60
- 239000000017 hydrogel Substances 0.000 title claims abstract description 58
- 230000008439 repair process Effects 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title abstract description 33
- 229920001661 Chitosan Polymers 0.000 claims abstract description 77
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract description 22
- 230000007547 defect Effects 0.000 claims abstract description 16
- 229910001427 strontium ion Inorganic materials 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 14
- 239000002262 Schiff base Substances 0.000 claims abstract description 12
- 125000003277 amino group Chemical group 0.000 claims abstract description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 12
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 11
- 239000010452 phosphate Substances 0.000 claims abstract description 11
- 238000007259 addition reaction Methods 0.000 claims abstract description 7
- 150000004753 Schiff bases Chemical class 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 80
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical group [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 42
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- 235000011176 polyphosphates Nutrition 0.000 claims description 3
- 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 description 2
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- 229920002000 Xyloglucan Polymers 0.000 abstract description 74
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- 238000000502 dialysis Methods 0.000 description 18
- 241000596504 Tamarindus Species 0.000 description 13
- 235000004298 Tamarindus indica Nutrition 0.000 description 13
- -1 cationic polysaccharide Chemical class 0.000 description 13
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
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- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 description 11
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- 230000037180 bone health Effects 0.000 description 2
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- 235000013619 trace mineral Nutrition 0.000 description 2
- 239000011573 trace mineral Substances 0.000 description 2
- GJKGAPPUXSSCFI-UHFFFAOYSA-N 2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Chemical compound CC(C)(O)C(=O)C1=CC=C(OCCO)C=C1 GJKGAPPUXSSCFI-UHFFFAOYSA-N 0.000 description 1
- 208000027205 Congenital disease Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229920002488 Hemicellulose Polymers 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical group OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
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- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
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- 238000007037 hydroformylation reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 1
- WTNTZFRNCHEDOS-UHFFFAOYSA-N n-(2-hydroxyethyl)-2-methylpropanamide Chemical compound CC(C)C(=O)NCCO WTNTZFRNCHEDOS-UHFFFAOYSA-N 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000000016 photochemical curing Methods 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- JOPDZQBPOWAEHC-UHFFFAOYSA-H tristrontium;diphosphate Chemical compound [Sr+2].[Sr+2].[Sr+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O JOPDZQBPOWAEHC-UHFFFAOYSA-H 0.000 description 1
- 125000000969 xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 description 1
Landscapes
- Materials For Medical Uses (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention provides a natural polysaccharide hydrogel for bone repair, a preparation method and a use method thereof. The natural polysaccharide is modified to prepare aldehyde modified xyloglucan and double bond modified chitosan, and the Schiff base reaction between aldehyde and amino groups of the chitosan is utilized to construct hydrogel based on a dynamic covalent cross-linked network, so that the hydrogel can be directly injected into irregular bone defect positions for filling. Under the photoinitiation condition, double bonds in the hydrogel undergo addition reaction to form a second cross-linked network structure based on covalent bonds, so that the elastic modulus of the material is improved. The active substances strontium ions and phosphate are loaded in the hydrogel, the microelement strontium ions play an important role in maintaining the health of natural bones, and can promote the proliferation and differentiation of osteoblasts and the formation of blood vessels, and the phosphate is the main component of bone tissues, so that the phosphate is matched with the strontium ions to jointly promote the bone repair.
Description
Technical Field
The invention belongs to the field of biomedical polymer materials, and particularly relates to a natural polysaccharide hydrogel for bone repair, and a preparation method and a use method thereof.
Background
Bone is an important supporting structure of human body, for light and small range of bone injury, bone tissue can restore health through self-repairing ability, but in more cases, bone injury caused by trauma, infection, tumor, osteomyelitis operation debridement, some congenital diseases and other reasons cannot be self-repaired, so that the incidence rate of bone injury is increased, and huge economic pressure and psychological burden are brought to patients.
With the development of tissue engineering technology, bone tissue engineering plays an important role in repairing bone defects, and can promote bone tissue growth, repair bone defects and present bioactive substances. The hydrogel is used as a water-containing three-dimensional network polymer and consists of natural or synthetic polymers, has good toughness, and particularly the natural polysaccharide hydrogel has high water retention capacity, good biocompatibility, biodegradability and no toxicity, and is an excellent material for bone repair. Therefore, the natural polysaccharide hydrogel can simulate a natural tissue environment, provide structural support for a defect part and promote the repair of the bone defect part. In particular to injectable hydrogel which can adapt to different shapes of bone defect parts and is cured by in-situ photocrosslinking, and has unique advantages.
Xyloglucan (XG) extracted from tamarind seed is hemicellulose, is a main component of higher plant cell wall, is a natural branched polysaccharide, and has main chain composed of glucose ring and side chain with xylose ring and galactose ring with bioactive function. Chitosan (CS), a cationic polysaccharide containing a large number of amino groups, has biodegradability, biocompatibility, antibacterial activity and hemostatic ability, and has been widely used in tissue engineering, drug delivery and injectable hydrogels.
The trace element strontium ion plays an important role in maintaining natural bone health, can promote osteoblast proliferation and differentiation and angiogenesis, and has physiological functions closely related to bone formation. Phosphate is the main component of bone tissue, and the phosphate is matched with strontium ions to promote bone repair together.
Disclosure of Invention
The application provides a natural polysaccharide hydrogel for bone repair, which meets the requirements of bone defects of different shapes, and the loaded strontium ions and phosphate can promote osteoblast proliferation and differentiation and angiogenesis. Two natural polysaccharides, namely xyloglucan and chitosan, are selected as raw materials, and are subjected to hydroformylation modification and methacrylamide modification respectively. The Schiff base reaction between aldehyde group and amino group is utilized to construct a dynamic covalent network, and then the covalent network is constructed in situ by photoinitiated double bond polymerization, so that the injectable hydrogel with flexibly regulated rheological property and mechanical property is prepared. The good injectability also provides application prospect for 3D biological printing.
According to a first aspect of the present application, there is provided a method of preparing a natural polysaccharide hydrogel for bone repair, comprising:
(1) Mixing a solution A containing an aldehyde natural polysaccharide and a solution B containing a double-bond modified chitosan derivative, wherein aldehyde groups in the aldehyde natural polysaccharide and amino groups in the double-bond modified chitosan derivative react with each other through Schiff base to obtain a dynamic covalent network of the polysaccharide hydrogel;
(2) Carrying out addition reaction on the dynamic covalent network of the polysaccharide hydrogel obtained in the step (1) under the irradiation of ultraviolet light to obtain natural polysaccharide hydrogel containing double cross-linked networks and used for bone repair;
the solution A comprises any one of a bone repair promoter and a mixture E;
the solution B comprises the other one of a bone repair accelerant and the mixture E;
the mixture E comprises strontium ions and a photoinitiator.
Specifically, in the step (1), strontium ions are combined with phosphate ions in the bone repair agent to form strontium phosphate.
Optionally, the bone repair agent is selected from at least one of polyphosphate and phosphate.
Optionally, the aldehyde-modified natural polysaccharide is selected from at least one of aldehyde-modified xyloglucose and aldehyde-modified hyaluronic acid;
the strontium ion is selected from strontium chloride hexahydrate;
the double bond modified chitosan derivative is methacrylated chitosan.
Optionally, the mass content of the initiator is 0.1-1.0% in the added raw materials (double bond modified chitosan derivative, aldehyde modified xyloglucan, strontium chloride hexahydrate, sodium polyphosphate, initiator).
Optionally, the polyphosphate is selected from sodium polyphosphate; the phosphate is selected from sodium phosphate.
Optionally, the mass ratio of the double bond modified chitosan derivative, the aldehyde natural polysaccharide, the strontium ions and the bone accelerator is 0.5-2:1-2:0.1-1.5:0.1-2.
Optionally, the photoinitiator is selected from at least one of phenyl-2, 4, 6-trimethyl benzoyl lithium phosphate, 2-hydroxy-2-methyl-1-phenyl acetone, 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 2' -azo (2-methyl-N- (2-hydroxyethyl) propionamide).
As an embodiment of the present application, the preparation method includes:
step one), performing oxidation reaction on xyloglucan to obtain aldehyde group modified xyloglucan; dissolving aldehyde-modified xyloglucan in water to obtain an aldehyde-modified xyloglucan water solution; adding sodium polyphosphate, and stirring to obtain a uniform solution;
step two), chitosan reacts with methacrylic anhydride to obtain a double bond modified chitosan derivative; dissolving a double-bond modified chitosan derivative in water to obtain a double-bond modified chitosan derivative aqueous solution; adding strontium chloride hexahydrate and a photoinitiator, and stirring to obtain a uniform solution;
step three), mixing the aqueous solution of the aldehyde group modified xyloglucan in the step one) and the aqueous solution of the double bond modified chitosan derivative in the step two), and generating a dynamic covalent network through Schiff base reaction to obtain the natural polysaccharide hydrogel capable of being injected for bone repair.
Optionally, the mass ratio of the double bond modified chitosan derivative to the aldehyde-modified natural polysaccharide is 1:0.5 to 2.0.
Optionally, the preparation method of the aldehyde-modified natural polysaccharide comprises the following steps:
and (3) reacting the aqueous solution containing the natural polysaccharide with an oxidant to obtain the aldehyde natural polysaccharide.
Preferably, the oxidizing agent is selected from sodium periodate.
Optionally, the concentration of the natural polysaccharide in the aqueous solution containing the natural polysaccharide and the oxidant is 0.5 to 2.0wt%; the concentration of the oxidant is 0.1-3 wt%.
Alternatively, the conditions of the reaction are: and (3) carrying out light-shielding reaction for 2-12 h.
Optionally, the preparation method of the aldehyde-modified natural polysaccharide comprises the following steps:
the xyloglucan and the sodium periodate react for 2 to 12 hours in the water solution in the dark, and then the glycol is added to terminate the reaction.
As an embodiment of the present application, the preparation method of the double bond modified chitosan derivative comprises the following steps:
the aqueous solution containing chitosan derivative, glacial acetic acid and methacrylic anhydride reacts for 2 to 6 hours at the temperature of 60 to 70 ℃, and then the pH value is regulated to 6.0 to 7.0.
Optionally, the preparation method of the aqueous solution containing chitosan, glacial acetic acid and methacrylic anhydride comprises the following steps: adding 2-6 parts by volume of glacial acetic acid and 1-4 parts by volume of methacrylic anhydride into 200-400 parts by volume of 0.5-2.0 wt% chitosan aqueous solution, and uniformly mixing.
In the application, the natural polysaccharide hydrogel containing the double-crosslinked network for bone repair is solid and has no fluidity, and can be used conveniently in the step (2) under the light-shielding condition to obtain the hydrogel without double bond polymerization, and the hydrogel without double bond polymerization has fluidity, can adapt to the shape of the defect part, and is favorable for filling irregular-shape bone defects. Then, external light irradiation is carried out to increase the modulus of the material and prevent the material from flowing.
According to a second aspect of the present application, there is provided a natural polysaccharide hydrogel for bone repair selected from any one of the natural polysaccharide hydrogels for bone repair prepared according to the above method.
According to a third aspect of the present application, there is provided a method for using the above-mentioned natural polysaccharide hydrogel for bone repair, wherein the step (2) of preparing the natural polysaccharide hydrogel for bone repair is performed under a light-shielding condition, so as to obtain a material G without an addition reaction;
injecting the material G which does not undergo addition reaction to a bone defect position, and then adopting ultraviolet irradiation to promote wound healing; or,
and taking the material G as a biological 3D printing raw material, carrying out 3D printing manufacturing by irradiating the material G with ultraviolet light, and placing the material G at a bone defect position.
Compared with the prior art, the invention has the following beneficial effects:
the invention relates to a natural polysaccharide hydrogel with bioactivity for repairing bones, which is rich and easy to obtain based on natural polysaccharide. Aldehyde group modified xyloglucan is prepared by modifying natural polysaccharide. The Schiff base reaction between aldehyde group and amino group of chitosan is utilized to construct a cross-linked network based on dynamic covalent bonds, so that the cross-linked network has good injectability and self-repairing property, can be matched with the requirements of different bone defect positions, provides structural support for the defect positions after in-situ photocuring, and promotes the repair of the bone defect positions. The trace element strontium ion plays an important role in maintaining natural bone health, can promote osteoblast proliferation and differentiation and angiogenesis, and has physiological functions closely related to bone formation. Phosphate is the main component of bone, and phosphate is matched with strontium ions to promote bone repair.
Drawings
FIG. 1 is a schematic structural diagram of methacryloylated chitosan;
FIG. 2 is a schematic structural diagram of xyloglucan;
FIG. 3 is an EDS spectrum test chart of the hydrogel prepared in example 1. Wherein (a) is a microstructure of the hydrogel; (b) is the distribution of element C; (c) is the distribution of element O; (d) is the distribution of element N; (e) is the distribution of the element Sr; (f) is the distribution of the element P.
Detailed Description
The present application is described in detail below with reference to examples, but the present application is not limited to these examples.
Unless otherwise indicated, all starting materials in the examples of the present application were purchased commercially.
FIG. 1 is a schematic structural diagram of methacryloylated chitosan in the present application; FIG. 2 is a schematic structural diagram of xyloglucan.
The initiators used in the examples were all phenyl-2, 4, 6-trimethylbenzoyl lithium phosphate.
Example 1
Step one: preparation of tamarind xyloglucan
(1) 10g of tamarind powder is weighed and dissolved in 1000mL of deionized water, and stirred at 40 ℃ for 24 hours until a viscous solution is formed;
(2) Centrifuging the viscous solution, collecting supernatant, and removing insoluble impurities and proteins;
(3) Slowly adding the supernatant into excessive ethanol to obtain xyloglucan precipitate, and drying after three precipitation processes to obtain the purified xyloglucan raw material.
Step two: preparation of aldehyde xyloglucan
(1) 3.0g of xyloglucan is weighed and dissolved in 300mL of deionized water to obtain 1.0wt% xyloglucan solution;
(2) Weighing 0.3g of sodium periodate, adding the sodium periodate into the solution, and stirring for 2 hours in a dark place to perform oxidation reaction;
(3) Sucking 0.5mL of glycol, adding the glycol into the solution, reacting for 6 hours, and removing unreacted sodium periodate;
(4) And (3) putting the reacted solution into a 8000D dialysis bag, dialyzing for 3-5 days to remove impurities, and freeze-drying to obtain aldehyde modified xyloglucan.
Step three: preparation of methacryloylated chitosan
(1) Weighing 3g of chitosan (with deacetylation degree of 95%) and placing in 300mL of deionized water, dropwise adding 4mL of acetic acid to assist dissolution, stirring until the chitosan is completely dissolved, and heating to 60 ℃;
(2) 2mL of methacrylic anhydride is absorbed and added into the solution drop by drop, and the reaction is carried out for 3 hours at 60 ℃;
(3) Dropwise adding 10wt% sodium bicarbonate aqueous solution, neutralizing excessive acid, adjusting pH to 6.5, and stirring overnight to reduce bubble generation;
(4) And (3) putting the reacted solution into a 8000D dialysis bag for dialysis for 4 days, and freeze-drying to obtain the methacryloyl chitosan.
Step four: preparation of polysaccharide hydrogels
(1) Dissolving 0.2g of aldehyde-modified xyloglucan in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 6.0wt% to obtain an aldehyde-modified xyloglucan aqueous solution; on this basis, 0.1g of sodium polyphosphate was added and stirred to obtain a homogeneous solution.
(2) Dissolving 0.3g of the methacryloyl chitosan derivative in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 1.5wt% to obtain a double bond modified chitosan derivative aqueous solution; on this basis, 0.1g strontium chloride hexahydrate and 5mg photoinitiator were added and stirred to give a homogeneous solution.
(3) Mixing the two obtained solutions according to the volume ratio of 1:1, and rapidly reacting amino groups on chitosan with aldehyde groups on xyloglucan to form Schiff base bonds, so as to obtain the non-covalent-based dynamic covalent-bond injectable hydrogel. After the gel is injected to a target position, double bond polymerization on chitosan is initiated in situ under blue light irradiation of 405nm to form a covalent network, so that the bioactive injectable natural polysaccharide hydrogel for bone repair based on the double network and with easily-controlled modulus is constructed.
Fig. 3 is an EDS spectrum test chart of the hydrogel prepared in this example. Wherein (a) is a microstructure of the hydrogel; (b) is the distribution of element C; (c) is the distribution of element O; (d) is the distribution of element N; (e) is the distribution of the element Sr; (f) is the distribution of the element P.
Example 2
Step one: preparation of tamarind xyloglucan
(1) 10g of tamarind powder is weighed and dissolved in 1000mL of deionized water, and stirred at 40 ℃ for 24 hours until a viscous solution is formed;
(2) Centrifuging the viscous solution, collecting supernatant, and removing insoluble impurities and proteins;
(3) Slowly adding the supernatant into excessive ethanol to obtain xyloglucan precipitate, and drying after three precipitation processes to obtain the purified xyloglucan raw material.
Step two: preparation of aldehyde xyloglucan
(1) 3.0g of xyloglucan is weighed and dissolved in 300mL of deionized water to obtain 1.0wt% xyloglucan solution;
(2) Weighing 0.3g of sodium periodate, adding the sodium periodate into the solution, and stirring for 2 hours in a dark place to perform oxidation reaction;
(3) Sucking 0.5mL of glycol, adding the glycol into the solution, reacting for 6 hours, and removing unreacted sodium periodate;
(4) And (3) putting the reacted solution into a 8000D dialysis bag, dialyzing for 3-5 days to remove impurities, and freeze-drying to obtain aldehyde modified xyloglucan.
Step three: preparation of methacryloylated chitosan
(1) Weighing 3g of chitosan (with deacetylation degree of 95%) and placing in 300mL of deionized water, dropwise adding 4mL of acetic acid to assist dissolution, stirring until the chitosan is completely dissolved, and heating to 60 ℃;
(2) 2mL of methacrylic anhydride is absorbed and added into the solution drop by drop, and the reaction is carried out for 3 hours at 60 ℃;
(3) Dropwise adding 10wt% sodium bicarbonate aqueous solution, neutralizing excessive acid, adjusting pH to 6.5, and stirring overnight to reduce bubble generation;
(4) And (3) putting the reacted solution into a 8000D dialysis bag for dialysis for 4 days, and freeze-drying to obtain the methacryloyl chitosan.
Step four: preparation of polysaccharide hydrogels
(1) Dissolving 0.3g of aldehyde-modified xyloglucan in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 6.0wt% to obtain an aldehyde-modified xyloglucan aqueous solution; on this basis, 0.2g of sodium polyphosphate was added and stirred to obtain a homogeneous solution.
(2) Dissolving 0.2g of the methacryloyl chitosan derivative in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 1.5wt% to obtain a double bond modified chitosan derivative aqueous solution; on this basis, 0.2g strontium chloride hexahydrate and 5mg photoinitiator were added and stirred to give a homogeneous solution.
(3) Mixing the two obtained solutions according to the volume ratio of 1:1, and rapidly reacting amino groups on chitosan with aldehyde groups on xyloglucan to form Schiff base bonds, so as to obtain the non-covalent-based dynamic covalent-bond injectable hydrogel. After the gel is injected to a target position, double bond polymerization on chitosan is initiated in situ under blue light irradiation of 405nm to form a covalent network, so that the bioactive injectable natural polysaccharide hydrogel for bone repair based on the double network and with easily-controlled modulus is constructed.
Example 3
Step one: preparation of tamarind xyloglucan
(1) 10g of tamarind powder is weighed and dissolved in 1000mL of deionized water, and stirred at 40 ℃ for 24 hours until a viscous solution is formed;
(2) Centrifuging the viscous solution, collecting supernatant, and removing insoluble impurities and proteins;
(3) Slowly adding the supernatant into excessive ethanol to obtain xyloglucan precipitate, and drying after three precipitation processes to obtain the purified xyloglucan raw material.
Step two: preparation of aldehyde xyloglucan
(1) 3.0g of xyloglucan is weighed and dissolved in 300mL of deionized water to obtain 1.0wt% xyloglucan solution;
(2) Weighing 0.3g of sodium periodate, adding the sodium periodate into the solution, and stirring for 2 hours in a dark place to perform oxidation reaction;
(3) Sucking 0.5mL of glycol, adding the glycol into the solution, reacting for 6 hours, and removing unreacted sodium periodate;
(4) And (3) putting the reacted solution into a 8000D dialysis bag, dialyzing for 3-5 days to remove impurities, and freeze-drying to obtain aldehyde modified xyloglucan.
Step three: preparation of methacryloylated chitosan
(1) Weighing 3g of chitosan (with deacetylation degree of 95%) and placing in 300mL of deionized water, dropwise adding 4mL of acetic acid to assist dissolution, stirring until the chitosan is completely dissolved, and heating to 60 ℃;
(2) 2mL of methacrylic anhydride is absorbed and added into the solution drop by drop, and the reaction is carried out for 3 hours at 60 ℃;
(3) Dropwise adding 10wt% sodium bicarbonate aqueous solution, neutralizing excessive acid, adjusting pH to 6.5, and stirring overnight to reduce bubble generation;
(4) And (3) putting the reacted solution into a 8000D dialysis bag for dialysis for 4 days, and freeze-drying to obtain the methacryloyl chitosan.
Step four: preparation of polysaccharide hydrogels
(1) Dissolving 0.3g of aldehyde-modified xyloglucan in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 6.0wt% to obtain an aldehyde-modified xyloglucan aqueous solution; on this basis, 0.2g of sodium polyphosphate was added and stirred to obtain a homogeneous solution.
(2) Dissolving 0.3g of the methacryloyl chitosan derivative in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 1.5wt% to obtain a double bond modified chitosan derivative aqueous solution; on this basis, 0.1g strontium chloride hexahydrate and 5mg photoinitiator were added and stirred to give a homogeneous solution.
(3) Mixing the two obtained solutions according to the volume ratio of 1:1, and rapidly reacting amino groups on chitosan with aldehyde groups on xyloglucan to form Schiff base bonds, so as to obtain the non-covalent-based dynamic covalent-bond injectable hydrogel. After the gel is injected to a target position, double bond polymerization on chitosan is initiated in situ under blue light irradiation of 405nm to form a covalent network, so that the bioactive injectable natural polysaccharide hydrogel for bone repair based on the double network and with easily-controlled modulus is constructed.
Example 4
Step one: preparation of tamarind xyloglucan
(1) 10g of tamarind powder is weighed and dissolved in 1000mL of deionized water, and stirred at 40 ℃ for 24 hours until a viscous solution is formed;
(2) Centrifuging the viscous solution, collecting supernatant, and removing insoluble impurities and proteins;
(3) Slowly adding the supernatant into excessive ethanol to obtain xyloglucan precipitate, and drying after three precipitation processes to obtain the purified xyloglucan raw material.
Step two: preparation of aldehyde xyloglucan
(1) 3.0g of xyloglucan is weighed and dissolved in 300mL of deionized water to obtain 1.0wt% xyloglucan solution;
(2) Weighing 0.45g of sodium periodate, adding the sodium periodate into the solution, and stirring for 2 hours in a dark place to perform oxidation reaction;
(3) Sucking 0.5mL of glycol, adding the glycol into the solution, reacting for 6 hours, and removing unreacted sodium periodate;
(4) And (3) putting the reacted solution into a 8000D dialysis bag, dialyzing for 3-5 days to remove impurities, and freeze-drying to obtain aldehyde modified xyloglucan.
Step three: preparation of methacryloylated chitosan
(1) Weighing 3g of chitosan (with deacetylation degree of 95%) and placing in 300mL of deionized water, dropwise adding 4mL of acetic acid to assist dissolution, stirring until the chitosan is completely dissolved, and heating to 60 ℃;
(2) 2mL of methacrylic anhydride is absorbed and added into the solution drop by drop, and the reaction is carried out for 3 hours at 60 ℃;
(3) Dropwise adding 10wt% sodium bicarbonate aqueous solution, neutralizing excessive acid, adjusting pH to 6.5, and stirring overnight to reduce bubble generation;
(4) And (3) putting the reacted solution into a 8000D dialysis bag for dialysis for 4 days, and freeze-drying to obtain the methacryloyl chitosan.
Step four: preparation of polysaccharide hydrogels
(1) Dissolving 0.2g of aldehyde-modified xyloglucan in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 6.0wt% to obtain an aldehyde-modified xyloglucan aqueous solution; on this basis, 0.25g of sodium polyphosphate was added and stirred to obtain a homogeneous solution.
(2) Dissolving 0.3g of the methacryloyl chitosan derivative in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 1.5wt% to obtain a double bond modified chitosan derivative aqueous solution; on this basis, 0.15g strontium chloride hexahydrate and 5mg photoinitiator were added and stirred to give a homogeneous solution.
(3) Mixing the two obtained solutions according to the volume ratio of 1:1, and rapidly reacting amino groups on chitosan with aldehyde groups on xyloglucan to form Schiff base bonds, so as to obtain the non-covalent-based dynamic covalent-bond injectable hydrogel. After the gel is injected to a target position, double bond polymerization on chitosan is initiated in situ under blue light irradiation of 405nm to form a covalent network, so that the bioactive injectable natural polysaccharide hydrogel for bone repair based on the double network and with easily-controlled modulus is constructed.
Example 5
Step one: preparation of tamarind xyloglucan
(1) 10g of tamarind powder is weighed and dissolved in 1000mL of deionized water, and stirred at 40 ℃ for 24 hours until a viscous solution is formed;
(2) Centrifuging the viscous solution, collecting supernatant, and removing insoluble impurities and proteins;
(3) Slowly adding the supernatant into excessive ethanol to obtain xyloglucan precipitate, and drying after three precipitation processes to obtain the purified xyloglucan raw material.
Step two: preparation of aldehyde xyloglucan
(1) 3.0g of xyloglucan is weighed and dissolved in 300mL of deionized water to obtain 1.0wt% xyloglucan solution;
(2) Weighing 0.45g of sodium periodate, adding the sodium periodate into the solution, and stirring for 2 hours in a dark place to perform oxidation reaction;
(3) Sucking 0.5mL of glycol, adding the glycol into the solution, reacting for 6 hours, and removing unreacted sodium periodate;
(4) And (3) putting the reacted solution into a 8000D dialysis bag, dialyzing for 3-5 days to remove impurities, and freeze-drying to obtain aldehyde modified xyloglucan.
Step three: preparation of methacryloylated chitosan
(1) Weighing 3g of chitosan (with deacetylation degree of 95%) and placing in 300mL of deionized water, dropwise adding 4mL of acetic acid to assist dissolution, stirring until the chitosan is completely dissolved, and heating to 60 ℃;
(2) Sucking 4mL of methacrylic anhydride, dropwise adding the methacrylic anhydride into the solution, and reacting for 3h at 60 ℃;
(3) Dropwise adding 10wt% sodium bicarbonate aqueous solution, neutralizing excessive acid, adjusting pH to 6.5, and stirring overnight to reduce bubble generation;
(4) And (3) putting the reacted solution into a 8000D dialysis bag for dialysis for 4 days, and freeze-drying to obtain the methacryloyl chitosan.
Step four: preparation of polysaccharide hydrogels
(1) Dissolving 0.2g of aldehyde-modified xyloglucan in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 6.0wt% to obtain an aldehyde-modified xyloglucan aqueous solution; on this basis, 0.3g of sodium polyphosphate was added and stirred to obtain a homogeneous solution.
(2) Dissolving 0.3g of the methacryloyl chitosan derivative in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 1.5wt% to obtain a double bond modified chitosan derivative aqueous solution; on this basis, 0.2g strontium chloride hexahydrate and 5mg photoinitiator were added and stirred to give a homogeneous solution.
(3) Mixing the two obtained solutions according to the volume ratio of 1:1, and rapidly reacting amino groups on chitosan with aldehyde groups on xyloglucan to form Schiff base bonds, so as to obtain the non-covalent-based dynamic covalent-bond injectable hydrogel. After the gel is injected to a target position, double bond polymerization on chitosan is initiated in situ under blue light irradiation of 405nm to form a covalent network, so that the bioactive injectable natural polysaccharide hydrogel for bone repair based on the double network and with easily-controlled modulus is constructed.
Example 6
Step one: preparation of tamarind xyloglucan
(1) 10g of tamarind powder is weighed and dissolved in 1000mL of deionized water, and stirred at 40 ℃ for 24 hours until a viscous solution is formed;
(2) Centrifuging the viscous solution, collecting supernatant, and removing insoluble impurities and proteins;
(3) Slowly adding the supernatant into excessive ethanol to obtain xyloglucan precipitate, and drying after three precipitation processes to obtain the purified xyloglucan raw material.
Step two: preparation of aldehyde xyloglucan
(1) 3.0g of xyloglucan is weighed and dissolved in 300mL of deionized water to obtain 1.0wt% xyloglucan solution;
(2) Weighing 0.3g of sodium periodate, adding the sodium periodate into the solution, and stirring for 2 hours in a dark place to perform oxidation reaction;
(3) Sucking 0.5mL of glycol, adding the glycol into the solution, reacting for 6 hours, and removing unreacted sodium periodate;
(4) And (3) putting the reacted solution into a 8000D dialysis bag, dialyzing for 3-5 days to remove impurities, and freeze-drying to obtain aldehyde modified xyloglucan.
Step three: preparation of methacryloylated chitosan
(1) Weighing 3g of chitosan (with deacetylation degree of 95%) and placing in 300mL of deionized water, dropwise adding 4mL of acetic acid to assist dissolution, stirring until the chitosan is completely dissolved, and heating to 60 ℃;
(2) 2mL of methacrylic anhydride is absorbed and added into the solution drop by drop, and the reaction is carried out for 3 hours at 60 ℃;
(3) Dropwise adding 10wt% sodium bicarbonate aqueous solution, neutralizing excessive acid, adjusting pH to 6.5, and stirring overnight to reduce bubble generation;
(4) And (3) putting the reacted solution into a 8000D dialysis bag for dialysis for 4 days, and freeze-drying to obtain the methacryloyl chitosan.
Step four: preparation of polysaccharide hydrogels
(1) Dissolving 0.2g of aldehyde-modified xyloglucan in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 6.0wt% to obtain an aldehyde-modified xyloglucan aqueous solution; on this basis, 0.25g of sodium polyphosphate was added and stirred to obtain a homogeneous solution.
(2) Dissolving 0.3g of the methacryloyl chitosan derivative in 10mL of deionized water, and stirring to form a uniform solution with the mass fraction of 1.5wt% to obtain a double bond modified chitosan derivative aqueous solution; on this basis, 0.15g strontium chloride hexahydrate and 5mg photoinitiator were added and stirred to give a homogeneous solution.
(3) Mixing the two obtained solutions according to the volume ratio of 1:1, and rapidly reacting amino groups on chitosan with aldehyde groups on xyloglucan to form Schiff base bonds, so as to obtain the non-covalent-based dynamic covalent-bond injectable hydrogel. After the gel is injected to a target position, double bond polymerization on chitosan is initiated in situ under blue light irradiation of 405nm to form a covalent network, so that the bioactive injectable natural polysaccharide hydrogel for bone repair based on the double network and with easily-controlled modulus is constructed.
The foregoing description is only a few examples of the present application and is not intended to limit the present application in any way, and although the present application is disclosed in the preferred examples, it is not intended to limit the present application, and any person skilled in the art may make some changes or modifications to the disclosed technology without departing from the scope of the technical solution of the present application, and the technical solution is equivalent to the equivalent embodiments.
Claims (10)
1. A method for preparing a natural polysaccharide hydrogel for bone repair, comprising:
(1) Mixing a solution A containing an aldehyde natural polysaccharide and a solution B containing a double-bond modified chitosan derivative, wherein aldehyde groups in the aldehyde natural polysaccharide and amino groups in the double-bond modified chitosan derivative react with each other through Schiff base to obtain a dynamic covalent network of the polysaccharide hydrogel;
(2) Carrying out addition reaction on the dynamic covalent network of the polysaccharide hydrogel obtained in the step (1) under the irradiation of ultraviolet light to obtain natural polysaccharide hydrogel containing double cross-linked networks and used for bone repair;
the solution A comprises any one of a bone repair promoter and a mixture E;
the solution B comprises the other one of a bone repair accelerant and the mixture E;
the mixture E comprises strontium ions and a photoinitiator.
2. The method according to claim 1, wherein the bone repair agent is at least one selected from the group consisting of polyphosphate and phosphate.
3. The method according to claim 1, wherein the aldehyde-modified natural polysaccharide is at least one selected from aldehyde-modified xyloglucose and aldehyde-modified hyaluronic acid;
the strontium ion is selected from strontium chloride hexahydrate;
the double bond modified chitosan derivative is methacrylated chitosan.
4. The method according to claim 1, wherein the mass ratio of the double bond modified chitosan derivative, the aldehyde-modified natural polysaccharide, the strontium ion and the bone accelerator is 0.5 to 2:1-2:0.1-1.5:0.1-2.
5. The method of claim 1, wherein the method of preparing the aldehyde-modified natural polysaccharide comprises:
and (3) reacting the aqueous solution containing the natural polysaccharide with an oxidant to obtain the aldehyde natural polysaccharide.
6. The method of claim 5, wherein the oxidizing agent is selected from sodium periodate.
7. The method according to claim 5, wherein the concentration of the natural polysaccharide in the aqueous solution containing the natural polysaccharide and the oxidizing agent is 0.5 to 2.0wt%; the concentration of the oxidant is 0.1-3 wt%.
8. The method according to claim 5, wherein the reaction conditions are: and (3) carrying out light-shielding reaction for 2-12 h.
9. A natural polysaccharide hydrogel for bone repair, wherein the natural polysaccharide hydrogel for bone repair is selected from any one of the natural polysaccharide hydrogels for bone repair prepared according to the method of any one of claims 1 to 8.
10. The method of using the natural polysaccharide hydrogel for bone repair according to claim 9, wherein the step (2) of claim 1 is performed under a dark condition to obtain a material G which is not subjected to addition reaction;
injecting the material G which does not undergo addition reaction to a bone defect position, and then adopting ultraviolet irradiation to promote wound healing; or,
and taking the material G as a biological 3D printing raw material, carrying out 3D printing manufacturing by irradiating the material G with ultraviolet light, and placing the material G at a bone defect position.
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