CN111467567A - Zwitterionic hyperbranched polyether hydrogel with high anti-fouling performance and preparation method and application thereof - Google Patents
Zwitterionic hyperbranched polyether hydrogel with high anti-fouling performance and preparation method and application thereof Download PDFInfo
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
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- C08J2487/00—Characterised by the use of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
Abstract
The invention discloses a zwitterionic hyperbranched polyether hydrogel with high anti-pollution performance and a preparation method and application thereof. The preparation method comprises the following steps: (1) synthesizing a betaine zwitterionic monomer containing double bonds; (2) synthesizing functional modified multi-arm polyethylene glycol; (3) synthesizing hyperbranched polyethylene glycol containing betaine zwitterion; (4) constructing hyperbranched polyethylene glycol hydrogel containing betaine zwitterion. The hydrogel carrier material prepared by the invention has excellent anti-fouling performance, can efficiently prevent biomolecules, cells and the like from contacting with gel, can realize low-concentration rapid in-situ gelling, further shows excellent biocompatibility and stability, is similar to a natural vitreous body in performance, and effectively meets the requirements of long-term stability and biocompatibility of a clinical operation vitreous body.
Description
Technical Field
The invention belongs to the technical field of hydrogel preparation, and particularly relates to a zwitterionic hyperbranched polyether hydrogel with high antifouling performance, and a preparation method and application thereof.
Background
Vitrectomy treatment of various eye disorders often requires the infusion of a filling material in place of the excised vitreous to support the vitreous cavity, maintain intraocular pressure, and play an important role in the prognosis of the disease and in preventing complications. At present, vitreous fillers for clinical use, such as gas, inflation gas, perfluorocarbon liquid, silicone oil and the like, cannot realize long-term filling, and toxic and side effects influence prognosis. The hydrogel based on zwitterions has excellent anti-pollution performance, so that biomolecules such as proteins and cells in eyes can be prevented from contacting with the gel, a series of complications including inflammation, infection, tissue fibrosis and the like can be avoided, the degradation time of the hydrogel can be prolonged, and the hydrogel has great potential for long-term filling of vitreous bodies. However, the use of zwitterionic hydrogels for vitreous filling typically requires in vitro gelling and re-injection into the vitreous cavity, and the injection process may destroy the mechanical properties of the hydrogel, thereby affecting the long-term vitreous filling effect in the eye. In addition, although the hydrogel commonly used at present, such as polyethylene glycol, polyvinyl alcohol, polyacrylic acid, polyacrylamide and the like, can realize in-situ gel forming filling, the problems of lack of anti-fouling performance, less reaction functional groups and the like cause long gel forming time, large gel forming concentration, easy degradation and are not beneficial to long-term filling application of clinical vitreous bodies. Therefore, the development of hydrogel which can be injected in situ, has the anti-pollution performance and can be filled with vitreous bodies for a long time has important clinical significance.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the zwitterionic hyperbranched polyether hydrogel with high antifouling performance, and the preparation method and the application thereof, which can effectively realize in-situ gelling and solve the problems of poor stability and insufficient antifouling performance of the conventional hydrogel.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
An application of zwitter-ion hyperbranched polyether hydrogel with high anti-pollution performance in filling or preparing a drug carrier after vitrectomy.
Further, the hydrogel is a zwitterionic hyperbranched polyethylene glycol hydrogel with high stain resistance.
The preparation method of the zwitterionic hyperbranched polyether hydrogel with high stain resistance comprises the following steps:
(1) Mixing and reacting betaine containing double bonds as a zwitterionic monomer with multi-arm polyethylene glycol with a sulfhydryl end in a molar ratio of 1-30: 1 to prepare the zwitterionic multi-arm polyethylene glycol with the sulfhydryl end;
(2) Mixing and reacting zwitterionic multi-arm polyethylene glycol with a mercapto group at the tail end with multi-arm polyethylene glycol with a double bond at the tail end in a molar ratio of 1: 0.01-0.95 to prepare zwitterionic hyperbranched polyethylene glycol with a mercapto group at the tail end;
(3) Mixing and reacting zwitterionic multi-arm polyethylene glycol with a mercapto group at the tail end with multi-arm polyethylene glycol with a double bond at a molar ratio of 0.05-0.95: 1 to prepare zwitterionic hyperbranched polyethylene glycol with a double bond at the tail end;
(4) dissolving the zwitterionic hyperbranched polyethylene glycol prepared in the step (2) and the step (3) to make the concentration of the zwitterionic hyperbranched polyethylene glycol 5-15 g/L, and then forming gel in situ at 15-37 ℃.
Further, the betaine containing double bonds is sulfobetaine containing double bonds or carboxylic betaine containing double bonds.
Further, the preparation method of the sulfobetaine containing double bonds comprises the following steps:
under the condition of stirring, dripping β -sultone monomer solution into an N- (N, N' -dimethylaminopropyl) acrylamide solution, reacting at normal temperature for 15-20 h in a protective gas atmosphere, filtering and washing a solid-phase product;
the mol ratio of β -sultone monomer to the N- (N, N' -dimethylaminopropyl) acrylamide is 1: 1-1.5.
The chemical reaction formula is as follows:
Further, the preparation method of the carboxylic acid betaine containing the double bond comprises the following steps:
under the condition of stirring, dripping β -propiolactone monomer solution into the N- (N, N' -dimethylaminopropyl) acrylamide solution, reacting at normal temperature for 20-30 h in a protective gas atmosphere, filtering and washing a solid-phase product;
the mol ratio of the β -propiolactone monomer to the N- (N, N' -dimethylaminopropyl) acrylamide is 1: 1-1.5.
The chemical reaction formula is as follows:
Further, the preparation method of the multi-arm polyethylene glycol with double bonds at the tail end or the multi-arm polyethylene glycol with sulfydryl at the tail end comprises the following steps:
Mixing the multi-arm polyethylene glycol and the components containing sulfydryl or double bonds in a molar ratio of 1: 4-30, and reacting at 40-80 ℃ for 24-60 hours.
Furthermore, the molecular weight of the multi-arm polyethylene glycol is 5000-40000, and the number of the arms is at least four.
Further, the component containing sulfydryl is thiourea; the double bond-containing component is 2-bromoethyl methacrylate.
The zwitterionic hyperbranched polyethylene glycol hydrogel with high stain resistance is prepared by the preparation method.
The invention has the beneficial effects that:
The hydrogel carrier material prepared by the invention has excellent anti-fouling performance, can efficiently prevent biomolecules, cells and the like from contacting with gel, can realize quick gelling within 5min at low concentration, further shows excellent biocompatibility and stability, is similar to a natural vitreous body in performance, and effectively meets the requirements of long-term stability and biocompatibility of fillers after a vitreous body operation.
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate the understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and it will be apparent to those skilled in the art that various changes may be made without departing from the spirit and scope of the invention as defined and defined in the appended claims, and all matters produced by the invention using the inventive concept are protected.
Example 1
A preparation method of a zwitterionic hyperbranched polyethylene glycol hydrogel with high anti-fouling performance comprises the following steps:
(1) Synthesis of Carboxylic betaine zwitterionic monomer containing double bond (CBMA)
dissolving N- (N, N' -dimethylaminopropyl) acrylamide (DMAPAA, 4.0g, 25.6mmol) in 10m L anhydrous acetone, then dissolving β -propiolactone monomer (2g, 27.8mmol) in 10m L anhydrous acetone, slowly dropwise adding the β -propiolactone monomer into an acetone solution of DMAPAA under the stirring condition of 500r/min, continuing reacting at normal temperature for 24 hours under the protection of nitrogen, filtering to obtain white precipitate after the reaction is finished, washing with acetone for three times, and then drying in vacuum to obtain the double-bond-containing zwitterionic monomer CBMA, wherein the chemical reaction formula is shown as follows.
(2) Synthesis of functionalized modified multi-arm polyethylene glycol
Mixing eight-arm polyethylene glycol (8sPEG, Mw ═ 20k) with thiourea and 2-bromoethyl methacrylate respectively in a molar ratio of 1:10, and reacting at 40 ℃ for 48h to respectively obtain the eight-arm polyethylene glycol with the tail ends of sulfydryl and double bonds;
Wherein, the structural formula of the eight-arm polyethylene glycol with the tail end being sulfhydryl group is as follows:
The structural formula of the eight-arm polyethylene glycol with the double bond at the tail end is as follows:
(3) Synthesis of carboxylic acid betaine zwitterion-containing hyperbranched polyethylene glycol
a. Preparing zwitterionic octagon polyethylene glycol (8sPEG-SH) with a terminal sulfhydryl group by Michael addition reaction of 1g (0.005 mmol) and Carboxylic Betaine (CBMA) containing a double bond, wherein the molar ratio of the 8sPEG-SH to the CBMA is 1: 4;
b. Reacting the product obtained in the step a with eight-arm polyethylene glycol with double bonds at the tail end to prepare zwitter-ion hyperbranched polyethylene glycol with double bonds at the tail end and containing carboxylic betaine, wherein the molar ratio of the product obtained in the step a to the eight-arm polyethylene glycol with double bonds at the tail end is 0.05: 1;
c. And b, mixing the product obtained in the step a and eight-arm polyethylene glycol with double bonds at the tail end in a molar ratio of 1:0.0125, and reacting to prepare the zwitter-ion hyperbranched polyethylene glycol with sulfhydryl at the tail end and containing carboxylic acid betaine.
(4) Construction of carboxylic acid betaine zwitterion-containing hyperbranched polyethylene glycol hydrogel
and (3) dissolving the product with the sulfhydryl end and the product with the double bond end obtained in the step (3) by PBS to ensure that the concentration of the products is 6 g/L, and then carrying out in-situ crosslinking at 37 ℃ within 5min to form the hyperbranched polyether hydrogel for intraocular glass filling.
Example 2
A preparation method of a zwitterionic hyperbranched polyethylene glycol hydrogel with high anti-fouling performance comprises the following steps:
(1) Synthesis of a double bond-containing sulfobetaine zwitterionic monomer (SBMA)
dissolving N- (N, N' -dimethylaminopropyl) acrylamide (DMAPAA, 2.0g, 12.8mmol) in 10m L anhydrous acetone, then dissolving β -sultone monomer (1g, 14.02mmol) in 10m L anhydrous acetone, slowly dropwise adding the β -sultone monomer into an acetone solution of DMAPAA under the stirring condition of 600r/min, continuing reacting at normal temperature for 18 hours under the protection of nitrogen, filtering to obtain white precipitate after the reaction is finished, washing with acetone for three times, and then drying in vacuum to obtain the double-bond-containing zwitterionic monomer SBMA, wherein the chemical reaction formula is shown as follows.
(2) Synthesis of functionally modified multi-arm polyethylene glycol
Mixing eight-arm polyethylene glycol (8sPEG, Mw ═ 10k) with thiourea and 2-bromoethyl methacrylate respectively in a molar ratio of 1:10, and reacting at 40 ℃ for 48h to respectively obtain the eight-arm polyethylene glycol with the tail ends of sulfydryl and double bonds;
Wherein, the structural formula of the eight-arm polyethylene glycol with the tail end being sulfhydryl group is as follows:
The structural formula of the eight-arm polyethylene glycol with the double bond at the tail end is as follows:
(3) Synthesis of hyperbranched polyethylene glycol containing sulfonic acid betaine zwitterion
a. Preparing zwitter-ion eight-arm polyethylene glycol (8sPEG-SH) with a terminal of sulfydryl (1g,0.0001mmol) and betaine Sulfonate (SBMA) containing double bonds through Michael addition reaction, wherein the molar ratio of the 8sPEG-SH to the CBMA is 1: 4;
b. Reacting the product obtained in the step a with eight-arm polyethylene glycol with double bonds at the tail end to prepare zwitter-ion hyperbranched polyethylene glycol with double bonds at the tail end and containing sulfobetaine, wherein the molar ratio of the product obtained in the step a to the eight-arm polyethylene glycol with double bonds at the tail end is 0.15: 1;
c. And (b) mixing the product obtained in the step (a) with eight-arm polyethylene glycol with double bonds at the tail end in a molar ratio of 1:0.0375 to react to prepare the zwitterionic hyperbranched polyethylene glycol with sulfhydryl at the tail end and containing betaine sulfonate.
(4) Construction of hyperbranched polyethylene glycol hydrogel containing sulfonic acid betaine zwitterion
and (3) dissolving the product with the sulfhydryl end and the product with the double bond end obtained in the step (3) by PBS to ensure that the concentration of the products is 8 g/L, and then carrying out in-situ crosslinking at 37 ℃ within 5min to form the hyperbranched polyether hydrogel for intraocular glass filling.
Example 3
A preparation method of a zwitterionic hyperbranched polyethylene glycol hydrogel with high anti-fouling performance comprises the following steps:
(1) Synthesis of Carboxylic betaine zwitterionic monomer containing double bond (CBMA)
dissolving N- (N, N' -dimethylaminopropyl) acrylamide (DMAPAA, 4.0g, 25.6mmol) in 15m L anhydrous acetone, then dissolving β -propiolactone monomer (1.5g, 20.4mmol) in 15m L anhydrous acetone, slowly dropwise adding the β -propiolactone monomer into an acetone solution of DMAPAA under the stirring condition of 800r/min, continuing reacting for 20 hours at normal temperature under the protection of nitrogen, filtering to obtain white precipitate after the reaction is finished, washing with acetone for three times, and drying in vacuum to obtain the double-bond-containing zwitterionic monomer CBMA, wherein the chemical reaction formula is shown as follows.
(2) Synthesis of functionally modified multi-arm polyethylene glycol
Mixing four-arm polyethylene glycol (4sPEG, Mw (equal to 10 k)) with thiourea and 2-bromoethyl methacrylate respectively in a molar ratio of 1:8, and reacting at 40 ℃ for 268h to respectively obtain four-arm polyethylene glycol with the tail ends of sulfydryl and double bonds;
Wherein, the structural formula of the four-arm polyethylene glycol with the tail end being sulfhydryl group is as follows:
The structural formula of the four-arm polyethylene glycol with the double bond at the tail end is as follows:
(3) Synthesis of carboxylic acid betaine zwitterion-containing hyperbranched polyethylene glycol
a. Preparing zwitterionic four-arm polyethylene glycol (4sPEG-SH) with a terminal sulfhydryl group by Michael addition reaction of 1g (0.005 mmol) and Carboxylic Betaine (CBMA) containing a double bond, wherein the molar ratio of the 4sPEG-SH to the CBMA is 1: 2;
b. Reacting the product obtained in the step a with four-arm polyethylene glycol with double bonds at the tail end to prepare zwitter-ion hyperbranched polyethylene glycol with double bonds at the tail end and containing carboxylic betaine, wherein the molar ratio of the product obtained in the step a to the four-arm polyethylene glycol with double bonds at the tail end is 0.35: 1;
c. And (b) mixing the product obtained in the step (a) with four-arm polyethylene glycol with double bonds at the tail end in a molar ratio of 1:0.0875 for reaction to prepare the zwitter-ion hyperbranched polyethylene glycol with sulfydryl at the tail end and containing carboxylic acid betaine.
(4) Construction of carboxylic acid betaine zwitterion-containing hyperbranched polyethylene glycol hydrogel
and (3) dissolving the product with the double bond at the tail end and the product with the sulfydryl at the tail end obtained in the step (3) by PBS to ensure that the concentrations of the products are 10 g/L, and then carrying out in-situ crosslinking at 25 ℃ within 5min to form the hyperbranched polyether hydrogel for filling the glass in the eyes.
Example 4
1. Protein adsorption Performance test
the hydrogel prepared in examples 1 to 3, methacrylamide zwitterionic hydrogel (control group 1) and a gel formed only by PEG (control group 2) were respectively placed in PNS solution with BSA-FITC concentration of 0.5mg/M L by taking BSA-FITC as a mimic protein, then placed in an SHA-C type digital display water bath constant temperature oscillator, oscillated at a constant speed of 37 ℃ for 6 hours, and then various hydrogel samples were taken out and continuously washed with PBS (pH 7.4,0.1M) of 5 × 1M L to remove BSA-FITC which is not adsorbed on the hydrogel surface, and then the protein adsorption amount on the hydrogel surface per unit area was calculated, and the results are shown in Table 1.
TABLE 1 protein adsorption on hydrogel surface
| Test item | Example 1 | Example 2 | Example 3 | Control group 1 | Control group 2 |
| BSA adsorption amount (ng/cm) 2) | 4.6 | 4.3 | 4.5 | 155 | 72 |
2. Cell adsorption Performance test
the hydrogels prepared in examples 1 to 3, control 1 and control 2 were prepared to have a diameter × height of 15mm × 2mm, respectively, and then soaked in alcohol and sterilized under an ultraviolet lamp for 0.5h, the hydrogels were washed twice with PBS (pH 7.4, 0.1M) and placed in a 24-well plate, after the cells were recovered, they were digested and blown off with 0.25% pancreatin, and then counted, 1M L containing 3 × 10 was dropped into each well containing the hydrogel 4DMEM medium of individual cells, then subjecting the hydrogel to a constant temperature environment of 37 ℃ in CO 2Culturing for 72h in an incubator, and observing the cell adhesion condition of the hydrogel surface under a BM-37XC binocular biomicroscope, wherein the hydrogel surfaces prepared in examples 1-3 have no cell adhesion basically, the control group 1 and the control group 2 both have cells adhered to the surfaces thereof, and the cell adhesion amount in the control group 2 is higher than that in the control group 1.
Therefore, according to the adsorption conditions of the hydrogel prepared in the embodiments 1 to 3 on proteins and cells, the hydrogel prepared in the application has excellent anti-fouling and anti-cell adhesion performances.
Example 5 in vivo gel stability testing in animals
Twenty-five female rabbits with the weight of 3-5 kg are equally divided into five groups, which are respectively marked as A, B, C, D, E, the left eye of each female rabbit is an experimental eye for operation, the right eye is a control, and slit lamp, fundus and intraocular pressure examination is performed before the operation to determine that no eye abnormality exists.
Performing three-channel closed type vitrectomy on the left eyes of all female rabbits, performing gas-liquid exchange after the vitrectomy, gelling the hydrogel prepared in the embodiment 1-3, the methacrylamide hydrogel and the PEG gel in vitro, injecting the hydrogel, the methacrylamide hydrogel and the PEG gel into the vitreous cavities of the left eyes of five groups of female rabbits with the label of A, B, C, D, E, and closing scleral incisions. After operation, the dianbizhi eye drops are dropped into the eye for 3 times every day, and the eye drops are observed by a slit lamp at regular intervals.
Observing the situation by using a postoperative slit lamp, wherein the inflammatory reaction does not appear in the left eye of A, B, C three groups of experimental rabbits after the operation, and the inflammatory reaction appears in the experimental rabbits marked as groups D and E; meanwhile, the vitreous bodies in the left eyes of A, B, C three groups of experimental rabbits are kept transparent within 15-16 weeks, and then are gradually degraded in the eyes, wherein the degradation time is more than 12 weeks; the vitreous body in the left eye of the experimental rabbit marked as group D keeps transparent within 10 weeks, then starts to degrade in the eye, and completely degrades within 3-5 weeks; the vitreous in the left eye of experimental rabbits designated as group E remained clear for 5-6 weeks, thereafter began to degrade in the eye and was completely degraded within 2 weeks.
Meanwhile, in the case of B-ultrasonic examination of eyes of A, B, C, D, E five groups of experimental rabbits, acoustic images such as vitreous opacity, hemorrhage, vitreous retinal fibroplasia, and retinal detachment were not detected.
The experimental results show that the zwitterionic hydrogel prepared by the invention is used as an intraocular filler to be filled into a vitreous cavity, has good compatibility, slow degradation speed, no obvious inflammatory reaction and good filling effect.
Claims (10)
1. An application of zwitter-ion hyperbranched polyether hydrogel with high anti-pollution performance in filling or preparing a drug carrier after vitrectomy.
2. The use according to claim 1, wherein the hydrogel is a zwitterionic hyperbranched polyethylene glycol hydrogel having high stain resistance.
3. The preparation method of the zwitterionic hyperbranched polyethylene glycol hydrogel with high anti-pollution performance as claimed in claim 2, which is characterized by comprising the following steps:
(1) Mixing and reacting betaine containing double bonds as a zwitterionic monomer with multi-arm polyethylene glycol with a sulfhydryl end in a molar ratio of 1-30: 1 to prepare the zwitterionic multi-arm polyethylene glycol with the sulfhydryl end;
(2) Mixing and reacting zwitterionic multi-arm polyethylene glycol with a mercapto group at the tail end with multi-arm polyethylene glycol with a double bond at the tail end in a molar ratio of 1: 0.01-0.95 to prepare zwitterionic hyperbranched polyethylene glycol with a mercapto group at the tail end;
(3) Mixing and reacting zwitterionic multi-arm polyethylene glycol with a mercapto group at the tail end with multi-arm polyethylene glycol with a double bond at a molar ratio of 0.05-0.95: 1 to prepare zwitterionic hyperbranched polyethylene glycol with a double bond at the tail end;
(4) Dissolving the zwitterionic hyperbranched polyethylene glycol prepared in the step (2) and the step (3), and then forming gel in situ at 15-37 ℃.
4. The method according to claim 3, wherein the double bond-containing betaine is a double bond-containing sulfobetaine or a double bond-containing carboxybetaine.
5. The method according to claim 4, wherein the method for preparing the double bond-containing sulfobetaine comprises the following steps:
under the condition of stirring, dripping β -sultone monomer solution into an N- (N, N' -dimethylaminopropyl) acrylamide solution, reacting at normal temperature for 15-20 h in a protective gas atmosphere, filtering and washing a solid-phase product;
the molar ratio of the β -sultone monomer to the N- (N, N' -dimethylaminopropyl) acrylamide is 1: 1-1.5.
6. The method according to claim 4, wherein the double bond-containing carboxylic acid betaine is prepared by:
under the condition of stirring, dripping β -propiolactone monomer solution into the N- (N, N' -dimethylaminopropyl) acrylamide solution, reacting at normal temperature for 20-30 h in a protective gas atmosphere, filtering and washing a solid-phase product;
the molar ratio of the β -propiolactone monomer to the N- (N, N' -dimethylaminopropyl) acrylamide is 1: 1-1.5.
7. The method of claim 3, wherein the double-bond-terminated multi-arm polyethylene glycol or the mercapto-terminated multi-arm polyethylene glycol is prepared by:
Mixing the multi-arm polyethylene glycol and the components containing sulfydryl or double bonds in a molar ratio of 1: 4-30, and reacting at 40-80 ℃ for 24-60 hours.
8. The method of claim 7, wherein the multi-arm polyethylene glycol has a molecular weight of 5000 to 40000 and a number of arms of at least four.
9. The method according to claim 7, wherein the mercapto group-containing component is thiourea; the double bond-containing component is 2-bromoethyl methacrylate.
10. The zwitterionic hyperbranched polyethylene glycol hydrogel with high stain resistance prepared by the preparation method of any one of claims 3-9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911313985.2A CN111467567A (en) | 2019-12-19 | 2019-12-19 | Zwitterionic hyperbranched polyether hydrogel with high anti-fouling performance and preparation method and application thereof |
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| CN113667141A (en) * | 2021-07-09 | 2021-11-19 | 深圳华源再生医学有限公司 | Alginate hydrogel for resisting protein adhesion and preparation method and application thereof |
| CN114767920A (en) * | 2022-05-13 | 2022-07-22 | 中国科学院长春应用化学研究所 | Polyethylene glycol-based adhesive and preparation method and application thereof |
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