CN112851966A - Double-modified compound and preparation method thereof, biological glue and preparation method thereof - Google Patents
Double-modified compound and preparation method thereof, biological glue and preparation method thereof Download PDFInfo
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- CN112851966A CN112851966A CN202011618494.1A CN202011618494A CN112851966A CN 112851966 A CN112851966 A CN 112851966A CN 202011618494 A CN202011618494 A CN 202011618494A CN 112851966 A CN112851966 A CN 112851966A
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Abstract
The invention is applicable to the technical field of compound synthesis, and provides a double-modified compound and a preparation method thereof, biological glue and a preparation method thereof. The basic skeleton adopted by the invention is gelatin, and the biological macromolecule with good biocompatibility is safe, nontoxic, biodegradable and high in biological safety; in addition, the biological glue prepared from the double modified compound contains aldehyde groups and methacrylic acid groups, wherein the aldehyde groups can chemically react with amino groups in biological tissues to generate a stable Schiff base structure to form a first-stage cross-linked network, the methacrylic acid groups can chemically react under the irradiation of ultraviolet light or blue-violet light to form gel, the gel is a second-stage cross-linked network, and the adhesion of the biological glue is remarkably increased through the two-stage cross-linked network, so that the purposes of adhering tissues, stopping bleeding and protecting wounds are achieved.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a double-modified compound and a preparation method thereof, and biological glue and a preparation method thereof.
Background
In surgery, it has been common to connect broken, ruptured blood vessels together with a needle and thread, but suturing is not suitable for particularly small blood vessels. The biological glue bonding means is to bond the tiny blood vessels by using the biological glue and can avoid some side effects of the suture.
The existing clinical application has the limit of using biological glue to adhere wounds for the purposes of adhering tissues, stopping bleeding and protecting the wounds. However, the types of the biological glue are few, and the biological glue is mostly composed of compound organic matters, tissue adhesion is completed through a series of chemical reactions, the existing biological glue generally adopts a single chemical crosslinking mode to adhere tissues, and meanwhile, one or more organic matters adopted cannot keep good biological safety or biological toxicity.
Therefore, the existing biological glue has the problems of weak adhesion and biological safety.
Disclosure of Invention
The embodiment of the invention aims to provide a double-modified compound, and aims to solve the problems of insecure adhesion and biological safety of the existing biological glue.
The embodiment of the invention is realized by using a double-modified compound, wherein the double-modified compound is obtained by using gelatin molecules as basic skeletons, modifying aldehyde groups on the gelatin molecules and grafting methacrylic acid molecules.
Another object of an embodiment of the present invention is a method of preparing a double modified compound, comprising:
adding gelatin powder and water into a reaction container, and heating and dissolving to obtain a gelatin solution;
adding sodium periodate into the gelatin solution, reacting for 8-15h at room temperature in a dark condition, adding ethylene glycol to stop the reaction, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain aldehyde gelatin;
adding water into the aldehyde gelatin, and heating and dissolving to obtain an aldehyde gelatin solution;
under the alkaline condition, adding methacrylic anhydride into the aldehyde gelatin solution, heating and reacting in a dark place, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain the gelatin.
Another object of an embodiment of the present invention is a biological glue comprising said double modified compound.
Another object of an embodiment of the present invention is to provide a method for preparing a biological glue, including:
mixing the double modified compound and a photoinitiator according to the weight ratio of 10: (0.01-1.5) are dissolved in water to obtain the biological glue.
The double-modified compound provided by the embodiment of the invention is obtained by taking gelatin molecules as basic skeletons, modifying aldehyde groups on the gelatin molecules and grafting methacrylic acid molecules; on one hand, the basic skeleton adopted by the invention is gelatin, which is a biological macromolecule with good biocompatibility, is safe, nontoxic, biodegradable and high in biological safety; on the other hand, the biological glue prepared from the double modified compound contains aldehyde groups and methacrylic acid groups, wherein the aldehyde groups can chemically react with amino groups in biological tissues to generate a stable Schiff base structure to form a first-stage cross-linked network, then the methacrylic acid groups chemically react under the irradiation of ultraviolet light or blue-violet light to form gel, the gel is a second-stage cross-linked network, and the adhesion of the biological glue is remarkably increased through the two-stage cross-linked network, so that the purposes of adhering tissues, stopping bleeding and protecting wounds are achieved.
Drawings
FIG. 1 is a schematic diagram of the synthesis of an aldehyde-based gelatin provided by an embodiment of the present invention;
FIG. 2 is a schematic diagram of the synthesis of an aldehydized and methacrylated gelatin provided by an embodiment of the present invention;
FIG. 3 shows NMR spectra of gelatin, aldehyde-modified gelatin, and methacrylated gelatin provided in examples of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention aims to solve the problems of insecure adhesion and biological safety of the existing biological glue, and provides a double-modified compound which is obtained by taking gelatin molecules as basic skeletons, modifying aldehyde groups on the gelatin molecules and grafting methacrylic acid molecules; on one hand, the basic skeleton adopted by the invention is gelatin, which is a biological macromolecule with good biocompatibility, is safe, nontoxic, biodegradable and high in biological safety; on the other hand, the biological glue prepared from the double modified compound contains aldehyde groups and methacrylic acid groups, wherein the aldehyde groups can chemically react with amino groups in biological tissues to generate a stable Schiff base structure to form a first-stage cross-linked network, then the methacrylic acid groups chemically react under the irradiation of ultraviolet light or blue-violet light to form gel, the gel is a second-stage cross-linked network, and the adhesion of the biological glue is remarkably increased through the two-stage cross-linked network, so that the purposes of adhering tissues, stopping bleeding and protecting wounds are achieved.
In the embodiment of the invention, the double-modified compound is an aldehyde-modified and methyl propionic acid-esterified gelatin which is obtained by modifying aldehyde groups on gelatin molecules and grafting methacrylic acid molecules by using the gelatin molecules as basic skeletons. The prior art does not report the related schemes of aldehyde-based and methacrylic acid-esterified gelatin and synthesis thereof, and the closest related report only refers to a synthesis method of methacrylic acid-esterified gelatin (GelMA), namely methacrylic acid molecules are adopted to be modified on gelatin molecules, and the gelatin molecules have photocuring crosslinking characteristics, and after a photoinitiator is added, the gelatin molecules can be used for preparing photosensitive hydrogel structures and 3D printing ink based on photocuring technology; however, GelMA can only form a photo-crosslinked gel structure by means of a photoinitiator, cannot adhere to biological tissues, and cannot serve as a biological glue.
In the examples of the present invention, the structural formula of the double modified compound is as follows:
the embodiment of the invention also provides a preparation method of the double modified compound, which comprises the following steps:
and step S1, adding gelatin powder and water into the reaction container for heating and dissolving to obtain gelatin solution.
In this embodiment of the present invention, the step S1 may be:
5-15g of gelatin powder and 100-300g of water are added into a reaction vessel, and the mixture is dissolved by magnetic stirring under the heating condition until the mixture is clear and transparent, so as to obtain a gelatin solution.
In the present examples, the gelatin is type a, 300 grams jelly strength (BLOOM value).
And step S2, adding sodium periodate into the gelatin solution, reacting for 8-15 hours at room temperature in a dark condition, adding ethylene glycol to stop the reaction, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain the aldehyde gelatin.
In this embodiment of the present invention, the step S2 may be:
adding 0.03-0.1mol of sodium periodate into the gelatin solution, reacting for 8-15h under magnetic stirring at room temperature in a dark place, adding 10-30mL of ethylene glycol to stop the reaction, putting the reactant into a dialysis bag, dialyzing in water at 30-60 ℃ until the reactant is odorless, colorless and transparent, changing distilled water for many times to improve dialysis efficiency, and finally collecting the solution in the dialysis bag and freeze-drying to obtain the aldehyde-based gelatin.
In the embodiment of the present invention, the reaction process of step S2 corresponds to the chemical equation shown in fig. 1.
In an embodiment of the invention, the dialysis bag has a molecular weight cut-off of 8 to 14 kilodaltons.
And step S3, adding water into the aldehyde gelatin, and heating and dissolving to obtain an aldehyde gelatin solution.
In this embodiment of the present invention, the step S3 may be:
adding 100g of water into 5-15g of the aldehyde gelatin, and magnetically stirring and dissolving at the temperature of 30-80 ℃ until the aldehyde gelatin is clear and transparent to obtain an aldehyde gelatin solution.
And step S4, adding methacrylic anhydride into the aldehyde gelatin solution under alkaline conditions, heating and reacting in a dark place sufficiently, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain the gelatin.
In this embodiment of the present invention, the step S4 may be:
adjusting the pH value of the aldehyde gelatin solution to 7.5-8.5, adding 3-6mL of methacrylic anhydride, maintaining the pH value of the solution to 7.5-8.5, continuously stirring and reacting for 2-5h in a dark magnetic field at the temperature of 30-50 ℃, putting the reactant into a dialysis bag, dialyzing in water at the temperature of 40-60 ℃ until the reactant is odorless, colorless and transparent, replacing distilled water for many times to improve the dialysis efficiency, and finally collecting the solution in the dialysis bag for freeze drying to obtain the product.
In the embodiment of the present invention, the reaction process of step S4 corresponds to the chemical equation shown in fig. 2.
The embodiment of the invention also provides the biological glue which comprises the double-modified compound.
The embodiment of the invention also provides a preparation method of the biological glue, which comprises the following steps:
mixing the double modified compound and a photoinitiator according to the weight ratio of 10: (0.01-1.5) and finally controlling the concentration to be 5% -30% to obtain the biological glue.
In the embodiment of the present invention, the photoinitiator is 2-Hydroxy-4 '- (2-hydroxyethoxy) -2-methyl propiophenone (2-Hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone) or an aqueous solution of lithium phenyl-2,4, 6-trimethylbenzoylphosphonate (lithophenyl-2, 4, 6-trimethylbenzoylphosphonate). When the photoinitiator is the aqueous solution of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone, the double modified compound and the photoinitiator are mixed according to the weight ratio of 10: (0.5-1.5) dissolving in water to obtain biological glue; when the photoinitiator is the aqueous solution of phenyl-2,4,6-trimethyl benzoyl lithium phosphonate, the double modified compound and the photoinitiator are mixed according to the weight ratio of 10: (0.01-0.1) is dissolved in water to obtain the biological glue.
Examples of certain embodiments of the invention are given below, which are not intended to limit the scope of the invention.
In addition, it should be noted that the numerical values given in the following examples are as precise as possible, but those skilled in the art will understand that each numerical value should be understood as a divisor rather than an absolutely exact numerical value due to measurement errors and experimental operational problems that cannot be avoided. For example, due to errors in the weighing apparatus, it should be understood that the weight values of the respective raw materials in the respective examples may have errors of ± 2% or ± 1%.
Example 1: synthesis of Aldehyde gelatin (Gel-Aldehyde)
Adding 200 g of distilled water into 10 g of gelatin (type A, 300g of jelly strength (BLOOM value)) powder, and magnetically stirring and heating to 60 ℃ for dissolving until the mixture is clear and transparent; adding 0.06mol of sodium periodate, and magnetically stirring in a dark place to react for 12 hours at room temperature; adding 20 ml of glycol to stop the reaction; then putting into dialysis bag (with molecular weight cut-off of 8-14 kilodalton) and dialyzing in 50 deg.C distilled water for 3 days, and replacing distilled water every 12 hr; and finally, collecting the solution in the dialysis bag, and freeze-drying to obtain the aldehyde gelatin. The synthesis equation of the Aldehyde gelatin (Gel-Aldehyde) is shown in FIG. 1.
Example 2: synthesis of Aldehyde and methylacrylic acid esterified gelatin (GelMA-Aldehyde)
10 g of the aldehyde gelatin synthesized in example 1 was added with 100g of distilled water, magnetically stirred and heated to 60 ℃ to be dissolved until the gelatin is clear and transparent; subsequently adjusting the pH value to 8 by using 1mol per liter (mol/L) of sodium hydroxide solution; then adding 4 ml of methacrylic anhydride, and maintaining the pH value of the solution at 8; continuously reacting for 5 hours at 40 ℃ by magnetic stirring in a dark place; then putting into a dialysis bag (with molecular weight cutoff of 8-14 kilodalton), dialyzing in 50 deg.C distilled water for 5 days in dark place, and replacing distilled water every 12 hr; and finally, collecting the solution in the dialysis bag, and freeze-drying to obtain the GelMA-Aldehyde. The synthesis equation of the aldehydized and methacrylated gelatin (GelMA-Aldehyde) is shown in FIG. 2.
Example 3: synthesis of Aldehyde and methylacrylic acid esterified gelatin (GelMA-Aldehyde)
Adding 100g distilled water into 5g gelatin (type A, 300g jelly strength (BLOOM value)) powder, magnetically stirring, and heating to 60 deg.C for dissolving until it is clear and transparent; adding 0.03mol of sodium periodate, and magnetically stirring in a dark place to react for 8 hours at room temperature; then 10 ml of ethylene glycol is added to stop the reaction; then putting into a dialysis bag (with molecular weight cutoff of 8-14 kilodalton) and dialyzing in 30 deg.C distilled water for 3 days, and replacing distilled water every 12 hr; and finally, collecting the solution in the dialysis bag, and freeze-drying to obtain the aldehyde gelatin.
10 g of aldehyde gelatin is added with 100g of distilled water, and the mixture is magnetically stirred and heated to 60 ℃ to be dissolved until the mixture is clear and transparent. Subsequently adjusting the pH value to 8 by using 1mol per liter (mol/L) of sodium hydroxide solution; then adding 4 ml of methacrylic anhydride, and maintaining the pH value of the solution at 8; continuously reacting for 3 hours at 40 ℃ by magnetic stirring in a dark place; then putting into a dialysis bag (with molecular weight cutoff of 8-14 kilodalton), dialyzing in distilled water of 40 deg.C in the dark for 5 days, changing distilled water every 12 hr, and finally collecting the solution in the dialysis bag and freeze-drying to obtain GelMA-Aldehyde.
Example 4: synthesis of Aldehyde and methylacrylic acid esterified gelatin (GelMA-Aldehyde)
Adding 300g of distilled water into 15g of gelatin (type A, 300g of jelly strength (BLOOM value)) powder, and magnetically stirring and heating to 60 ℃ for dissolving until the mixture is clear and transparent; adding 0.1mol of sodium periodate, and magnetically stirring in a dark place to react for 15 hours at room temperature; adding 30ml of ethylene glycol to stop the reaction; then putting into dialysis bag (with molecular weight cut-off of 8-14 kilodalton) and dialyzing in distilled water of 30-60 deg.C for 3 days, and replacing distilled water every 12 hr; and finally, collecting the solution in the dialysis bag, and freeze-drying to obtain the aldehyde gelatin.
Adding 10 g of aldehyde gelatin into 100g of distilled water, magnetically stirring and heating until the aldehyde gelatin is dissolved at 60 ℃ until the aldehyde gelatin is clear and transparent; subsequently adjusting the pH value to 8 by using 1mol per liter (mol/L) of sodium hydroxide solution; then 4 ml of methacrylic anhydride were added and the solution pH was maintained at 8. Continuously reacting for 3 hours at 40 ℃ by magnetic stirring in a dark place; then putting into a dialysis bag (with molecular weight cutoff of 8-14 kilodalton), dialyzing in distilled water of 40 deg.C in the dark for 5 days, changing distilled water every 12 hr, and finally collecting the solution in the dialysis bag and freeze-drying to obtain GelMA-Aldehyde.
Example 5: preparation of photo-curable GelMA-Aldehyde aqueous solution
I2959 solution: 1 g of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone was dissolved in 100 ml of purified water.
And (3) dissolving 10 g of the GelMA-Aldehyde compound synthesized in the embodiment 2 in 100 ml of I2959 solution to obtain the biological glue.
Example 6: preparation of photo-curable GelMA-Aldehyde aqueous solution
LAP solution: 0.1 g of lithium phenyl-2,4, 6-trimethylbenzoylphosphonate is dissolved in 100 ml of purified water.
And (3) dissolving 10 g of the GelMA-Aldehyde compound synthesized in the embodiment 2 in 100 ml of LAP solution to obtain the biological glue.
In summary, the present invention in examples 1 to 4 was synthesized from gelatin to obtain an aldehyde-modified gelatin, and then synthesized to obtain an aldehyde-modified and methacrylated gelatin. FIG. 3 shows the 1H Nuclear Magnetic Resonance (NMR) spectra of Gelatin (Gelatin) and the synthesized Aldehyde Gelatin (Gel-Aldehyde), Aldehyde and methacrylated Gelatin (gelMA-Aldehyde) in example 1-2 of the present invention, wherein A is Gelatin (Gelatin); b is Aldehyde gelatin (Gel-Aldehyde); c is Aldehyde and methacrylate gelatin (GelMA-Aldehyde); 4.1ppm is the characteristic absorption peak of the aldehyde group; 5.4-5.6ppm are characteristic absorption peaks for Methacrylate (MA). It is noted that the prior art only currently accomplishes the synthesis of GelMA. The invention realizes that Aldehyde group is modified on GelMA to form a new compound GelMA-Aldehyde. The invention firstly adopts sodium periodate to oxidize two adjacent hydroxyl groups (-OH) on the gelatin into aldehyde groups (═ O). The added methacrylic anhydride can perform condensation reaction with amino on the gelatin to graft on the amino to form methacrylate, and finally the double-modified compound of the hydroformylation and the methacrylation esterified gelatin is formed.
The GelMA-Aldehyde aqueous solution prepared in the embodiment 5 can be used for photocuring reaction, and the photocuring reaction can be triggered within 15-20 seconds within the wavelength range of ultraviolet 350-370 nm; the GelMA-Aldehyde aqueous solution prepared in the embodiment 6 of the invention can be used for photocuring reaction, and the photocuring reaction can be triggered within 1-5 seconds within the wavelength range of 390-410nm of blue light.
The embodiment of the invention successfully synthesizes a novel double modified compound, namely hydroformylation and methacrylate esterified gelatin (GelMA-Aldehyde). The new compound takes gelatin molecules as basic skeleton, modifies aldehyde groups and grafts methacrylic acid molecules; the aldehyde group is easy to react with the amino group to form a Schiff base stable structure, and the methacrylic acid group is photosensitive. The Aldehyde and methacrylate gelatin (GelMA-Aldehyde) can be adhered to the surface of biological tissue rich in amino, and has photocuring crosslinking characteristic to form hydrogel. Therefore, the GelMA-Aldehyde aqueous solution has the function of biological glue, forms a firm hydrogel structure through two chemical crosslinking modes, and can be used for rapid wound adhesion.
In summary, compared with the prior art, the invention has the following advantages:
1. the crosslinking strength is high. The compound GelMA-Aldehyde was formylated and methacrylated. After the water solution is added with a photoinitiator, aldehyde groups can react with amino groups in biological tissues to generate chemical bonds so as to be adhered to the tissues; the methacrylic group is subjected to a crosslinking reaction under the irradiation of ultraviolet light or blue-violet light to form a hydrogel structure; the two-stage crosslinking reaction can increase the effect of the biological glue; the purposes of adhering tissues, stopping bleeding and protecting wounds are achieved.
2. The biological glue has simple components. Two-stage crosslinking can be realized by only adding a small amount (less than 0.5%) of photoinitiator into the aqueous solution of GelMA-Aldehyde, and the use is convenient and efficient.
The main framework of GelMA-Aldehyde is gelatin. Has good biocompatibility, safety, no toxicity, biodegradability and biosafety.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. The double-modified compound is characterized in that gelatin molecules are used as basic skeletons, and aldehyde groups are modified on the gelatin molecules and methacrylic acid molecules are grafted on the gelatin molecules to obtain the double-modified compound.
2. The double-modified compound of claim 1, wherein the structural formula of the double-modified compound is as follows:
3. a method for preparing a double-modified compound, comprising:
adding gelatin powder and water into a reaction container, and heating and dissolving to obtain a gelatin solution;
adding sodium periodate into the gelatin solution, reacting for 8-15h at room temperature in a dark condition, adding ethylene glycol to stop the reaction, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain aldehyde gelatin;
adding water into the aldehyde gelatin, and heating and dissolving to obtain an aldehyde gelatin solution;
under the alkaline condition, adding methacrylic anhydride into the aldehyde gelatin solution, heating and reacting in a dark place, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain the gelatin.
4. The method for preparing the double modified compound according to claim 3, wherein the step of adding gelatin powder and water into a reaction vessel for heating and dissolving to obtain a gelatin solution comprises the following steps:
5-15g of gelatin powder and 100-300g of water are added into a reaction vessel, and the mixture is dissolved by magnetic stirring under the heating condition until the mixture is clear and transparent, so as to obtain a gelatin solution.
5. The preparation method of the double modified compound as claimed in claim 3, wherein the step of adding sodium periodate into the gelatin solution, reacting for 8-15h at room temperature in the dark, adding ethylene glycol to stop the reaction, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain the aldehyde gelatin comprises the following steps:
adding 0.03-0.1mol of sodium periodate into the gelatin solution, magnetically stirring the mixture for reaction for 8-15h at room temperature in a dark place, adding 10-30mL of ethylene glycol to stop the reaction, putting the reactant into a dialysis bag, dialyzing the reactant in water at 30-60 ℃ until the reactant is odorless, colorless and transparent, and freeze-drying the reactant to obtain the aldehyde gelatin.
6. The method for preparing a double-modified compound according to claim 3, wherein the step of adding water to the aldehyde-modified gelatin for heating and dissolving to obtain an aldehyde-modified gelatin solution comprises the following steps:
adding 100g of water into 5-15g of the aldehyde gelatin, and magnetically stirring and dissolving at the temperature of 30-80 ℃ until the aldehyde gelatin is clear and transparent to obtain an aldehyde gelatin solution.
7. The preparation method of the double modified compound according to claim 3, wherein the method comprises the steps of adding methacrylic anhydride into the aldehyde gelatin solution under alkaline conditions, carrying out heating and light-proof reaction, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain the double modified compound, wherein the steps comprise:
adjusting the pH value of the aldehyde gelatin solution to 7.5-8.5, adding 3-6mL of methacrylic anhydride, maintaining the pH value of the solution to 7.5-8.5, continuously stirring and reacting for 2-5h in a dark magnetic field at the temperature of 30-50 ℃, then filling the reactant into a dialysis bag, dialyzing in water at the temperature of 40-60 ℃ until the reactant is odorless, colorless and transparent, and freeze-drying to obtain the compound.
8. A biogenic glue, characterized in that it comprises the double modified compound of claim 1.
9. A preparation method of biological glue is characterized by comprising the following steps:
reacting the double-modified compound of claim 1 with a photoinitiator in a ratio of 10: (0.01-1.5) are dissolved in water to obtain the biological glue.
10. The method of claim 9, wherein the photoinitiator is an aqueous solution of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone or lithium phenyl-2,4, 6-trimethylbenzoylphosphonate.
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