CN115920120A - Hydrogel compound for promoting regenerative healing of wound and preparation method thereof - Google Patents
Hydrogel compound for promoting regenerative healing of wound and preparation method thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention relates to a hydrogel compound for promoting regenerative healing of wounds and a preparation method thereof. The hydrogel compound is based on dopamine grafted gelatin and carboxymethyl chitosan, and uses end-diphenylformaldehyde functionalized polyethylene glycol as a cross-linking substance; the preparation method comprises the steps of mixing a dopamine grafted gelatin solution and a carboxymethyl chitosan solution under a vortex, and adding a dibenzoaldehyde-terminated functional polyethylene glycol solution into the vortex to mix. The hydrogel compound provided by the invention can also load drugs, and antibodies and growth factors with different dosages can be added according to the needs. The preparation method of the hydrogel compound provided by the invention is quick and simple, and is beneficial to large-scale industrial preparation; the prepared hydrogel composite has injectability and self-healing property, good mechanical property and good biocompatibility, and the in vitro cell level and the experimental animal level verify that the hydrogel composite promotes the proliferation of fibroblasts and the wound is healed more quickly and functionally.
Description
Technical Field
The invention relates to the field of medical dressings, in particular to a hydrogel composite for promoting regenerative healing of wounds and a preparation method thereof.
Background
Once damaged, the wound repair process of skin tissue is elaborate and complex, including: hemostasis, inflammation, cell proliferation, angiogenesis, connective tissue formation, wound contraction, and skin scarring is the ultimate result of repair after tissue injury. Wound dressings therefore play an important role in the wound healing process, in protecting wounds from external harmful factors, in forming an effective barrier in wound protection, and in accelerating wound healing.
However, although conventional dressings such as gauze and bandage have a certain function in hemostasis, absorbing wound exudate, protecting wound surface, etc., they have poor viscosity and need additional material for fixation, so that they do not have the function of actively promoting wound repair, and may cause leakage and adhesive crusting, which easily causes secondary injury, thus preventing the wound from healing faster and better.
The existing various wound dressings including hydrogel dressings have obvious effect of promoting wound healing, but most of the dressings have no good capability of promoting the growth of accessory organs such as hair follicles and the like, and cannot promote the functional healing of wounds.
Chitosan (CS) is a natural biopolymer, has good biocompatibility and biodegradability, can induce cell proliferation, promote hemostasis and tissue repair, and is widely applied to wound treatment. Carboxymethyl chitosan (CMCS) is an anionic derivative of chitosan, has better water solubility than chitosan, and has the advantages of no toxicity, low immunogenicity, biocompatibility, biodegradability and the like.
Document 1: CN 202111481051.7A preparation method of graphene oxide modified carboxymethyl chitosan composite hydrogel and application 2022.03.11. An ion crosslinking method is adopted, firstly, a graphene oxide dispersion solution is added into a carboxymethyl chitosan solution in proportion, uniformly mixed, added with triphosphoric acid and added with gelatin to obtain the composite hydrogel material which has a larger specific surface area, has better swelling property, thermal stability, biocompatibility and pH sensitivity, is used as a slow release material, improves the attachment site of a medicament, improves the medicament loading rate and has better medicament controlled release performance. However, the hydrogel has no injectability and self-healing property, cannot adapt to complicated and various wound types, and cannot verify the effect of the hydrogel on animals.
Disclosure of Invention
The present invention aims to provide a hydrogel composite for promoting regenerative healing of a wound, which is formed by Schiff base reaction and has excellent self-healing properties, and a preparation method thereof.
In order to realize the purpose of the invention, the technical solution is provided as follows: as shown in fig. 1, a hydrogel composite for promoting regenerative healing of a wound comprises dopamine grafted gelatin Gel-DA, carboxymethyl chitosan CMCS and dibenzoaldehyde-terminated functionalized polyethylene glycol DF-PEG; the adhesive is prepared by mixing 5wt% of dopamine grafted gelatin solution, 6wt% of carboxymethyl chitosan solution and 20wt% of terminal benzaldehyde functionalized polyethylene glycol solution; the volume ratio of the dopamine grafted gelatin solution to the carboxymethyl chitosan solution to the terminal benzaldehyde functionalized polyethylene glycol solution is 5.
The hydrogel compound is prepared by mixing a dopamine grafted gelatin solution and a carboxymethyl chitosan solution and then adding an aldehyde functionalized polyethylene glycol solution for mixing.
The invention also provides a preparation method of the hydrogel composite for promoting regenerative healing of wounds, which comprises the following steps:
s1, dissolving gelatin in deionized water, adding dopamine hydrochloride, adding EDC and NHS, and performing amidation reaction to obtain dopamine grafted gelatin;
s2, dissolving polyethylene glycol, 4-formylbenzoic acid and 4-dimethylaminopyridine in an organic solvent, adding N, N-dicyclohexylcarbodiimide under the protection of inert gas, stirring, and carrying out esterification reaction to obtain dibenzoaldehyde-terminated functionalized polyethylene glycol DF-PEG;
s3, dissolving carboxymethyl chitosan CMCS in deionized water to obtain a carboxymethyl chitosan CMCS solution;
s4, dissolving the dopamine grafted gelatin prepared in the step S1 in deionized water to obtain a Gel-DA solution;
s5, dissolving the dibenzoaldehyde-terminated functionalized polyethylene glycol DF-PEG prepared in the step S2 in deionized water to obtain a dibenzoaldehyde-terminated functionalized polyethylene glycol DF-PEG solution;
s6, adding the dopamine grafted gelatin solution obtained in the step S4 and the carboxymethyl chitosan solution obtained in the step S3 into a container at the same time, mixing in a vortex mode, adding the terminal benzaldehyde functionalized polyethylene glycol solution prepared in the step S5, and mixing to obtain a final product.
Further, the vortex speed is 2000 rpm in step S6.
Further, the temperature at which gelatin is dissolved in step S1 is 60 ℃.
Further, in step S2, the organic solvent is anhydrous tetrahydrofuran.
Further, in step S2, the inert gas is one or more of nitrogen, helium, neon and argon. Preferably nitrogen.
The invention also provides application of the hydrogel composite for promoting regenerative healing of wounds in preparation of the wound dressing.
The hydrogel composite provided by the invention can also load drugs; the drug is loaded by the following method: the preparation method comprises the following steps of carrying out vortex mixing on a dopamine grafted gelatin solution and a carboxymethyl chitosan solution, adding a medicine solution, carrying out ultrasonic mixing, and then adding a terminal benzaldehyde functionalized polyethylene glycol solution, and carrying out vortex mixing. The medicine refers to antibodies and growth factors with different dosages configured according to requirements, and 5ug/ml of antibody Lrig1 and 3ug/ml of growth factor IGF1 are added into the hydrogel compound through ultrasonic mixing.
Compared with the prior art, the invention has the following remarkable advantages:
(1) The hydrogel compound provided by the invention can be prepared only by mixing three solutions, and the method is quick and simple and is beneficial to large-scale industrial preparation;
(2) The hydrogel compound provided by the invention has injectability and self-healing performance, is formed by Schiff base reaction, and is subjected to breakage and reconnection of covalent bonds dynamically generated in a hydrogel network based on dynamic balance between the Schiff base and reactants containing aldehyde groups and amino groups, so that the hydrogel compound has excellent self-healing performance;
(3) The hydrogel composite provided by the invention has good biocompatibility, and the in vitro cell level and the experimental animal level verify that the hydrogel composite promotes the proliferation of fibroblasts and the wound healing is faster and more functional.
Drawings
Fig. 1 is a schematic view of the molecular structure of the hydrogel composite provided by the present invention.
Fig. 2 is a photograph of injectability and adhesion of a hydrogel composite provided by the present invention:
wherein FIG. 2A is a photograph of a hydrogel composite that may be injected with a needle; fig. 2B is a photograph of a hydrogel composite injected on a pigskin; fig. 2C is a photograph of a bent pigskin to which the hydrogel composite is adhered.
Figure 3 is a graph of the self-healing properties of a hydrogel composite provided by the present invention.
Fig. 4 is a Scanning Electron Microscope (SEM) photograph of a hydrogel composite provided by the present invention.
FIG. 5 is a photograph of a staining of dead cells of a hydrogel composite provided by the present invention.
Figure 6 is a photograph of the hydrogel composite provided by the present invention that facilitates fibroblast migration.
Figure 7 is a photograph of the hydrogel composite provided by the present invention promoting wound healing in mice.
Figure 8 is a photograph of HE, masson trichrome staining of a wound in a mouse with a hydrogel complex provided by the present invention.
Detailed Description
The present invention will be better understood from the following examples. However, it is readily understood by those skilled in the art that the specific material proportions, process conditions and results thereof described in the examples are merely illustrative of the invention and should not, nor should they limit the invention as detailed in the claims.
1. The main reagents are as follows:
gelatin (Type A from pig skin) was purchased from Sigma-Aldrich.
Dopamine hydrochloride (DA), N-hydroxysuccinimide (NHS), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) were purchased from Aladdin reagents, inc. (shanghai, china).
4-formylbenzoic acid, 4-Dimethylaminopyridine (DMAP), N, N-Dicyclohexylcarbodiimide (DCC), carboxymethyl chitosan (CMCS) was purchased from Michelin Biochemical technologies, inc. (shanghai, china).
Polyethylene glycol (PEG) (Mw = 2000), hydrochloric acid (HCl), tetrahydrofuran (THF) were purchased from pharmaceutical chemicals, ltd (shanghai, china). Tetrahydrofuran (THF) was treated with metallic sodium under reflux to dehydrate to give anhydrous tetrahydrofuran.
Deionized water was supplied by southern Jiangnan university.
2. The skin required for human fibroblast extraction was provided by the subsidiary hospital of south of the Yangtze university.
The culture method of the fibroblast comprises the following steps: skin specimens were washed, cut into small pieces, and digested with 0.1% collagenase I for 4h at 37 ℃. The cells were then suspended at 37 ℃ and 5% CO 2 In medium (DMEM containing 10% FBS, penicillin and streptomycin). Cells from 2 to 5 passages were used in the experiments.
3. Experimental animals: ICR mice were purchased from changzhou kavens laboratory animals ltd.
EXAMPLE 1 preparation of hydrogel composites
The preparation method of the hydrogel composite comprises the following steps:
(1) Dopamine grafted gelatin Gel-DA was prepared by dissolving gelatin completely in deionized water at 60 ℃ and keeping it under nitrogen. Subsequently, 2.0g of EDC and 1.2g of NHS were slowly added to the above solution, and after stirring for 30min, 4.0g of DA was added to the reaction system, and reacted at 37 ℃ for 24 hours. The pH of the solution was maintained at 5.5-6.0 throughout the reaction and the solution was protected under a stream of nitrogen. The mixture was then dialyzed against water for 3 days to completely remove unreacted reagents and salts, and finally the dialysate was lyophilized to give Gel-DA, which was stored at-20 ℃. By passing 1 HNMR spectroscopy in deuterium oxide (D) 2 O) and it was confirmed that the reaction gave Gel-DA.
(2) Preparing dialdehyde functionalized polyethylene glycol (DF-PEG), and synthesizing by esterification of PEG and 4-formylbenzoic acid, which specifically comprises the following steps: mixing PEG 2000 4-formylbenzoic acid and 4-Dimethylaminopyridine (DMAP) in anhydrous Tetrahydrofuran (THF); subsequently, N-Dicyclohexylcarbodiimide (DCC) was added in a nitrogen atmosphere and stirred at room temperature (20 ℃) for 20 hours, and filtered to obtain a white solid; it was then repeatedly dissolved in THF and precipitated in ether 3 times. Filtering and drying in a vacuum oven at room temperature to obtain the final white product, namely DF-PEG.
(3) Dissolving the lyophilized Gel-DA obtained in step (1) in deionized water to obtain a 5wt% Gel-Da solution; dissolution of CMCS in deionized water to yield a 6wt% CMCS solution; DF-PEG was dissolved in deionized water to obtain 2 wt% DF-PEG. After 2.5ml of gel-DA solution and 2.5ml of CMCS solution were mixed well, 1ml of DF-PEG solution was added and mixed vigorously by vortexing with a 2000 rpm stirrer to produce a hydrogel composite (labeled as PDC) within 1-2 min.
As shown in fig. 4, microscopic imaging of the hydrogel composite using Scanning Electron Microscopy (SEM) revealed that the hydrogel had a loose porous microstructure.
As shown in FIG. 2A, the hydrogel composite obtained is placed in the lumen of a syringe and slowly pressed outward to release the hydrogel composite through the syringe, and the shape of the hydrogel composite can be controlled manually.
As shown in fig. 2B and 2C, when the hydrogel composite is injected on the surface of the pigskin, the hydrogel composite has good adhesion, and can still adhere to the surface of the pigskin even if the pigskin is bent by 180 degrees.
Example 2 preparation of hydrogel Complex Supported antibody Lrig1
A hydrogel composite was prepared by the same procedure as in example 1, except that in step (3): dissolving the lyophilized Gel-DA obtained in step (1) in deionized water to obtain a 5wt% Gel-Da solution, dissolving CMCS in deionized water to obtain a 6wt% CMCS solution, and dissolving DF-PEG in deionized water to obtain a 2 wt% DF-PEG. After 2.5ml gel-DA solution and 2.5ml CMCS solution were mixed well, 5ug/ml antibody Lrig1 was added, sonicated for two minutes to mix well, then 1ml DF-PEG solution was added and mixed vigorously by vortexing with a 2000 rpm stirrer. The hydrogel complex-loaded antibody Lrig1 (labeled PDC @ Lrig 1) is formed within 1-2 min.
Example 3 preparation of hydrogel Complex Supported antibody Lrig1 and growth factor IGF1
A hydrogel composite was prepared by the same procedure as in example 1, except that in step (3): dissolving the lyophilized Gel-DA obtained in step (1) in deionized water to obtain a 5wt% Gel-Da solution, dissolving CMCS in deionized water to obtain a 6wt% CMCS solution, and dissolving DF-PEG in deionized water to obtain a 2 wt% DF-PEG. After 2.5ml of gel-DA solution and 2.5ml of CMCS solution were mixed well, 5ug/ml of antibody Lrig1 and 3ug/ml of growth factor IGF1 were added, mixed well by sonication for two minutes, and then 1ml of DF-PEG solution was added, and mixed vigorously by vortexing with a 2000 rpm shaker to form a hydrogel complex loaded with antibody Lrig1 and growth factor IGF1 (PDC @ Lrig1@ IGF1) within 1-2 min.
Example 4 self-healing test of hydrogel composites
The hydrogel composite prepared in example 1 was subjected to an alternating stress scan at 1rad/s using a DHR-3 rheometer, with the oscillating stress alternating between 1% and 600%, and measured continuously for 350s, as shown in figure 3. The results show that high strain force can destroy the hydrogel network structure, and at low strain, G' rapidly returns to the initial value, and the hydrogel is reconnected through covalent bonds to restore the normal structure. Therefore, the hydrogel can be rapidly self-repaired after the structural damage, and the hydrogel still can show the original structural performance after multiple times of damage and self-repair.
In addition, since the hydrogel composite prepared by the invention is formed by Schiff base reaction, based on the dynamic balance between Schiff base and reactants containing aldehyde groups and amino groups (DF-PEG reacts with two matrixes Gel-DA and CMCS), the breakage and reconnection of covalent bonds dynamically generated in the hydrogel network lead the hydrogel composite to have excellent self-healing performance.
Example 5 Effect of PDC hydrogel Complex, PDC @ Lrigg 1@ IGF1 on fibroblast Activity
The hydrogel complexes PDC, PDC @ lrig1, and igf1 obtained in examples 1,2, and 3 were sterilized, and then the three hydrogel complexes were immersed in DMEM cell culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at a concentration of 0.2g/ml for 24 hours; finally, the three soaked hydrogel complexes were diluted to 25% with fresh complete DMEM medium (pH 7.4).
Fibroblasts were seeded separately in 6-well plates and then incubated at 37 deg.C (5% CO) 2 ) And (3) culturing for 24h, adding the blank group and the extracts of the three hydrogel complexes into the cells after the cells are attached to the wall, incubating for a period of time, observing cell proliferation and morphology by calcein-AM/PI staining, observing the cells under a fluorescence microscope, and taking pictures.
As shown in fig. 5, calcein-AM/PI staining assay results showed that most cells in each group were green (i.e., live cells) and remained healthy at all time points, while a few cells were red (i.e., dead) (white bright spots in black-white plot). This indicates that the hydrogel composite provided by the present invention can support the growth of cells. In addition, the PDC, PDC @ Lrigg 1 and PDC @ Lrigg 1@ IGF-1 groups have higher living cell number and better cell morphology, and further prove that the hydrogel compound plus the antibody and the growth factor can promote the growth of fibroblasts, which indicates that the hydrogel compound provided by the invention has good biocompatibility.
Example 6 Effect of PDC hydrogel composite on fibroblast migration
The experiments for directed migration of fibroblasts were performed using 6-well plates. Fibroblast cells were cultured at 1X 10 5 The density of individual cells/well was seeded overnight in six-well culture dishes containing serum-free DMEM; thereafter, cells were removed from the center of the well using a cell scraper, and the cells were washed 3 times with PBS; finally, complete DMEM medium prepared in advance and containing PDC hydrogel complex, PDC @ Lrigg 1 and PDC @ Lrigg 1@ IGF-1 was added for incubation (the concentration of PDC hydrogel complex, PDC @ Lrigg 1 and PDC @ Lrigg 1@ IGF-1 was 25%). At 0h and 12hAnd 24h, observing the cells under a microscope and calculating the healing condition of the scratched area.
As shown in fig. 6, the results of the wound scratch test showed that the migration rate of fibroblasts in the PDC @ lrig1 and PDC @ lrig1@ igf1 groups was significantly faster than that in the blank control group and the PDC hydrogel group, indicating that the PDC hydrogel, PDC @ lrig1 and PDC @ lrig1@ igf1 could significantly accelerate the proliferation of fibroblasts and promote the healing of external scratches.
Example 7 evaluation of PDC hydrogel composite, PDC @ Lrigg 1@ IEF1 for wound healing in vivo
A subject: female ICR mice (7-8 weeks) were modeled as a mouse wound by total dorsal skin excision as follows:
animal grouping: the mice of the established wound model were divided into 4 mice of the blank control group, 4 mice of the PDC hydrogel group, 4 mice of the PDC @ Lrigg 1 group, and 4 mice of the PDC @ Lrigg 1@ IEF1 group according to the treatment mode. The blank control group was not treated at all. The hydrogel compositions 0.6ml prepared in example 1,2,3 were injected into a PDC hydrogel group, PDC @ Lrigg 1 group, and IEF1 group, respectively, and then applied to the wound with a syringe, and the composition was administered every three days. The mice were examined for wound status and photographed with a digital camera.
As shown in fig. 7, it can be seen that the macroscopic images of the wounds PDC @ lrig1 group and PDC @ lrig1@ igf1 group significantly decreased the wound area, and the PDC hydrogel group also consistently showed faster healing rates than the blank control group. On day 21, the facets of the PDC @ Lrigg 1 and PDC @ Lrigg 1@ IGF-1 groups healed almost completely. PDC hydrogels proved to accelerate wound healing and were readily available for clinical use.
As shown in FIG. 8, the wound tissues were histologically evaluated after 14 and 21 days, and it was found that the scar tissues were greatly reduced in the PDC group, the PDC @ Lrigg 1 group and the PDC @ Lrigg 1@ IGF1 group, compared with the blank control. For histological analysis, wound tissue was cut and fixed in 4% paraformaldehyde on day 14, embedded and processed in sections, and different sections were each H & E and Masson trichrome stained to study wound healing. HE. Masson trichrome staining showed that PDC hydrogel and Lrig1 and IGF1 treated wounds closed faster, and more skin appendages, such as blood vessels, hair follicles, appeared to promote wound functional healing. Overall, the PDC group, PDC @ Lrigg 1 group, and PDC @ Lrigg 1@ IGF-1 group promoted better wound healing with less scarring.
The above-mentioned embodiments only express several embodiments of the present application, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, which falls within the scope of protection of the present application. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A hydrogel composite for promoting regenerative healing of a wound, comprising: the hydrogel compound comprises dopamine grafted gelatin Gel-DA, carboxymethyl chitosan CMCS and diphenylaldehyde-terminated functionalized polyethylene glycol DF-PEG; the adhesive is prepared by mixing 5wt% of dopamine grafted gelatin solution, 6wt% of carboxymethyl chitosan solution and 20wt% of terminal benzaldehyde functionalized polyethylene glycol solution; the volume ratio of the dopamine grafted gelatin solution to the carboxymethyl chitosan solution to the terminal benzaldehyde functionalized polyethylene glycol solution is 5.
2. A hydrogel composite for promoting regenerative healing of a wound according to claim 1, wherein: the hydrogel compound is prepared by mixing a dopamine grafted gelatin solution and a carboxymethyl chitosan solution and then adding an aldehyde functionalized polyethylene glycol solution for mixing.
3. The method of claim 2, wherein the hydrogel composite for promoting regenerative wound healing comprises: the method comprises the following steps:
s1, dissolving gelatin in deionized water, adding dopamine hydrochloride, adding carbodiimide hydrochloride EDC and N-hydroxysuccinimide NHS, and performing amidation reaction to obtain Gel-DA;
s2, dissolving polyethylene glycol, 4-formylbenzoic acid and 4-dimethylaminopyridine in an organic solvent, adding N, N-dicyclohexylcarbodiimide under the protection of inert gas, stirring, and carrying out esterification reaction to obtain DF-PEG;
s3, dissolving CMCS in deionized water to obtain a CMCS solution;
s4, dissolving the Gel-DA prepared in the step S1 in deionized water to obtain a Gel-DA solution;
s5, dissolving the DF-PEG prepared in the step S2 in deionized water to obtain a DF-PEG solution;
and S6, simultaneously adding the Gel-DA solution obtained in the step S4 and the CMCS solution obtained in the step S3 into a container, carrying out vortex mixing, subsequently adding the DF-PEG solution prepared in the step S5, and mixing to obtain a final product.
4. A method of preparing a hydrogel composite for promoting regenerative healing of a wound according to claim 3, wherein: the vortex speed in step S6 is 2000 rpm.
5. A method of preparing a hydrogel composite for promoting regenerative healing of a wound according to claim 3, wherein: in step S1, the temperature at which gelatin is dissolved is 60 ℃.
6. A method of preparing a hydrogel composite for promoting regenerative healing of a wound according to claim 3, wherein: in step S2, the organic solvent is anhydrous tetrahydrofuran.
7. A method of preparing a hydrogel composite for promoting regenerative healing of a wound according to claim 3, wherein: in step S2, the inert gas is one or more of nitrogen, helium, neon, and argon.
8. Use of a hydrogel composite for promoting regenerative healing of a wound according to claim 2 in the preparation of a wound dressing.
9. The hydrogel composite for promoting regenerative healing of wound according to claim 2, wherein said hydrogel composite is further capable of supporting a drug;
the drug is loaded by the following method: vortex mixing Gel-DA solution and CMCS solution, adding the medicinal solution, ultrasonic mixing, and adding DF-PEG solution for mixing.
10. A hydrogel composite for promoting regenerative healing of a wound according to claim 9, wherein: the medicine is antibody Lrig1 and \ or growth factor IGF1.
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