CN111139594A - Preparation method of composite porous material for bone repair - Google Patents
Preparation method of composite porous material for bone repair Download PDFInfo
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- CN111139594A CN111139594A CN202010164731.5A CN202010164731A CN111139594A CN 111139594 A CN111139594 A CN 111139594A CN 202010164731 A CN202010164731 A CN 202010164731A CN 111139594 A CN111139594 A CN 111139594A
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- 239000011148 porous material Substances 0.000 title claims abstract description 34
- 239000002131 composite material Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 108010010803 Gelatin Proteins 0.000 claims abstract description 27
- 229920000159 gelatin Polymers 0.000 claims abstract description 27
- 239000008273 gelatin Substances 0.000 claims abstract description 27
- 235000019322 gelatine Nutrition 0.000 claims abstract description 27
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 21
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 20
- -1 silicon dioxide modified hydroxyapatite Chemical class 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000010041 electrostatic spinning Methods 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 76
- 238000003756 stirring Methods 0.000 claims description 35
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
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- 238000002156 mixing Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
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- 229910000831 Steel Inorganic materials 0.000 claims description 5
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 5
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- 238000001914 filtration Methods 0.000 claims description 5
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- 239000003431 cross linking reagent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
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- CCMKPCBRNXKTKV-UHFFFAOYSA-N 1-hydroxy-5-sulfanylidenepyrrolidin-2-one Chemical compound ON1C(=O)CCC1=S CCMKPCBRNXKTKV-UHFFFAOYSA-N 0.000 claims 1
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- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
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Abstract
The invention discloses a preparation method of a composite porous material for bone repair, belonging to the technical application field of biomedical materials, wherein gelatin and silicon dioxide modified hydroxyapatite whisker are adopted as raw materials, and an electrostatic spinning method is adopted to prepare the gelatin/silicon dioxide modified hydroxyapatite whisker composite porous material; the invention has simple process and convenient operation, and the prepared material not only has excellent biological property and mechanical strength, but also has an adjustable hole structure and has good application prospect in the aspect of bone repair materials.
Description
Technical Field
The invention relates to a preparation method of a composite porous material for bone repair, belonging to the field of bioengineering materials.
Background
Bone tissue is one of the few tissues that can clinically accomplish injury repair (fracture healing, etc.) in a regenerative manner, with the most critical being the practical application of membrane-guided bone tissue regeneration. The principle of the membrane-guided bone tissue regeneration technology is that the physical barrier function of a biological membrane is utilized to isolate a bone disease defect area from surrounding tissues, a relatively closed tissue environment is created, epithelial and fibrous tissues are prevented from growing into a bone wound area, an ideal bone regeneration healing space is ensured, bone tissue cell proliferation and repair are protected, the bone wound area is promoted to heal well and quickly, and the regeneration function of the bone tissues is exerted to the maximum extent. The bone repairing process guided by the membrane belongs to a natural bone regeneration process, and a new treatment way is opened up for bone reconstruction surgery by utilizing a tissue engineering technology and selecting a proper cell and membrane material.
Bone defects caused by various diseases such as osteonecrosis, tumors, wounds, infection and congenital deformity are common in clinic, but are difficult to treat. Currently, the common methods for clinically treating bone defects include autologous bone grafting and allogeneic bone grafting. The autologous bone is easy to accept by patients, but the injury and pain of secondary operation exist, the reaction of the affected area can be reduced to the maximum extent by autologous bone transplantation, but the bone taking amount is limited, and a series of potential complications such as wound of the supply area can be caused. The allogenic bone is simple and convenient in material obtaining, but has immunological rejection reaction and is likely to spread diseases for nearly two decades, and the principles of biology and tissue engineering are applied, high-concentration seed cells cultured in vitro are planted on a natural or artificially synthesized extracellular matrix carrier, induction factors are compounded, and then the seed cells are transplanted in vivo, so that the cell type tissue engineering artificial bone formed provides a new method for clinically treating bone defects.
Gelatin is a partial Collagen (Collagen) hydrolysate which has good biocompatibility and weak antigenicity, is fully biodegradable and also has relatively good viscosity and osteogenesis inducing effects. Besides a large number of hydroxyl groups, a plurality of carboxyl groups and amino groups are arranged on the side chain of the gelatin molecule, and the groups can generate great influence on the crystal structure and the appearance of the inorganic phase. Bigi et al used gelatin films to mimic collagen and poly (acrylic acid) to mimic natural acidic macro-macromolecules. After being soaked in the 1.5SBF solution for four days, the mineralization of spherical aggregate minerals appears on the gelatin film, the gelatin film HAs the morphology of ACP and the Ca/P ratio through X-ray diffraction, and the crystals grow in a preferred orientation and along the long axis direction, which indicates that collagen in the gelatin matrix HAs the potential of promoting the mineralization of HA.
Hydroxyapatite (Hydroxyapatite) is called HAP or HA for short, and molecular formula is Ca10(PO4)6(OH)2It is the main inorganic component of human skeleton. Hydroxyapatite has the characteristics of no toxicity, high strength, corrosion resistance, good affinity with bones and the like, and is widely applied to surgical operations such as artificial bones and the like at present. Compared with common hydroxyapatite, the hydroxyapatite whisker has higher surface activity and shows unique biological properties, and is also called as active hydroxyapatite.
Disclosure of Invention
The invention provides a preparation method of a composite porous material for bone repair, which is characterized in that gelatin and silicon dioxide modified hydroxyapatite are compounded through electrostatic spinning to prepare a nanofiber scaffold material with macropores of 1-20 microns.
A preparation method of a composite porous material for bone repair specifically comprises the following steps:
(1) mixing ethyl orthosilicate and absolute ethyl alcohol according to a volume ratio of 1: 5-10 to prepare a solution A, and mixing ammonia water and absolute ethyl alcohol according to a volume ratio of 1: 1-2 to prepare a solution B;
(2) stirring the solution B in a water bath environment at 40-50 ℃, dripping the solution A into the solution B, and after finishing dripping, continuously stirring and reacting to obtain silicon dioxide sol which is marked as solution C;
(3) mixing the hydroxyapatite whisker and absolute ethyl alcohol according to a mass volume ratio g: mL of 0.1-0.5: 1 to prepare a solution D, mixing the solution D and the solution C according to a volume ratio of 1: 5-10, aging, filtering, drying and sintering to obtain a silicon dioxide modified hydroxyapatite whisker;
(4) dissolving gelatin in glacial acetic acid at 40-90 ℃ according to the mass volume ratio g: mL of 10-20: 100 of the gelatin to the glacial acetic acid, and magnetically stirring for 3-5 h to obtain a gelatin solution;
(5) adding the silicon dioxide modified hydroxyapatite whiskers in the step (3) into the gelatin solution in the step (4), magnetically stirring for 6-12 hours, and finally dispersing for 1-3 hours by using an ultrasonic machine to obtain a spinning stock solution;
(6) and (3) adopting a flat receiver, connecting the positive electrode of a power supply with the needle head, connecting the negative electrode with a steel plate, carrying out electrostatic spinning on the spinning solution obtained in the step (5) to obtain spinning fibers, and crosslinking the spinning fibers by using a crosslinking agent to obtain the porous material for bone repair.
In the step (2), the stirring speed of the solution B is 100-200 r/min; the dropping speed of dropping the A liquid into the B liquid is 0.5-1 mL/min, wherein the volume ratio of the A liquid to the B liquid is 1: 1-2.
And (3) after the dropwise adding in the step (2) is finished, continuously stirring and reacting for 24-48 h, wherein the stirring speed is 100-200 r/min.
The aging time in the step (3) is 24-72 h.
And (3) drying in a vacuum or forced air drying mode at the drying temperature of 30-60 ℃ for 24 h.
And (3) sintering in an air atmosphere at 500 ℃ for 4-12 hours.
In the step (5), the mass-to-volume ratio g: mL of the silicon dioxide modified hydroxyapatite whisker to the gelatin solution is 0.1-0.5: 100.
The magnetic stirring speed of the step (4) and the step (5) is 100-200 r/min.
The electrostatic spinning conditions in the step (6) are as follows: the number of the used needle is 15-17, the advancing speed of the spinning solution is 0.1-0.2 mm/min, the positive voltage is 16-20 KV, the negative voltage is-3.5 KV, and the distance between the needle and the receiving device is 15-25 cm.
In the step (6), the cross-linking agent is a mixture of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxy sulphosuccinimide (EDC/NHS) in a mass ratio of 6:1 or glutaraldehyde; the crosslinking time is 24-36 h.
The invention has the beneficial effects that:
(1) the raw materials of the gelatin and the silicon dioxide modified hydroxyapatite crystal whisker have no cytotoxicity and good biocompatibility.
(2) The invention can better control the fiber quality and the fiber diameter distribution by changing relevant parameters of electrostatic spinning, and the structure is suitable for cell adhesion growth.
(3) The modified hydroxyapatite whisker prepared by the invention has excellent mechanical property and biological property.
(4) The modified hydroxyapatite whisker prepared by the invention has toughening effect on the electrostatic spinning film.
Drawings
Figure 1 is an SEM image of silica-modified hydroxyapatite whiskers of example 1;
FIG. 2 is an SEM photograph of the composite porous material for bone repair of example 1;
FIG. 3 is an SEM photograph of the composite porous material for bone repair of example 2;
fig. 4 is an SEM image of the composite porous material for bone repair of example 3.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
A preparation method of a composite porous material for bone repair specifically comprises the following steps:
(1) measuring 10mL of ethyl orthosilicate, stirring and dissolving in 100mL of absolute ethyl alcohol to obtain solution A, measuring 100mL of ammonia water, stirring and dissolving in 100mL of absolute ethyl alcohol to obtain solution B;
(2) stirring the solution B at the speed of 100r/min under the condition of water bath at the temperature of 40 ℃, dropwise adding the solution A into the solution B at the dropping speed of 0.5mL/min by a constant flow pump, wherein the volume ratio of the solution A to the solution B is 1:1, and after the dropwise adding is finished, continuously stirring and reacting for 24 hours, wherein the stirring speed is 100r/min, so as to obtain silicon dioxide sol which is marked as solution C;
(3) weighing 5g of hydroxyapatite whisker, ultrasonically dispersing in 50mL of absolute ethyl alcohol to prepare solution D, mixing the solution D and the solution C according to the volume ratio of 1:5, aging for 24h, filtering, drying for 24h at 30 ℃ in a vacuum drying oven, and sintering for 4h at 500 ℃ in an air atmosphere to obtain silicon dioxide modified hydroxyapatite whisker;
(4) dissolving 10g of gelatin in 100mL of glacial acetic acid at 40 ℃, and magnetically stirring for 3h at the speed of 200r/min to obtain a gelatin solution;
(5) adding 0.1g of the silicon dioxide modified hydroxyapatite whisker prepared in the step (3) into 100mL of the gelatin solution obtained in the step (4), magnetically stirring for 6 hours at the speed of 100r/min, and finally dispersing for 1 hour by using an ultrasonic machine to obtain a spinning stock solution;
(6) and (2) adopting a No. 15 needle, setting the positive voltage to be 16KV, the negative voltage to be-3.5 KV, setting the injection speed of the spinning solution to be 0.1mm/min, setting the distance between the needle and a receiving device to be 15cm, connecting the positive electrode of a power supply to the needle, connecting the negative electrode of the power supply to a steel plate, carrying out electrostatic spinning on the spinning solution obtained in the step (5) to obtain spinning fibers, and crosslinking the spinning fibers for 24h by adopting a mixture of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxy sulphosuccinimide (EDC/NHS) in a mass ratio of 6:1 to obtain the composite porous material for bone repair.
Fig. 1 is an SEM image of the silica-modified hydroxyapatite whisker prepared in step (3) of this example, and it is understood from the SEM image that silica is uniformly attached to the surface of hydroxyapatite.
FIG. 2 is an SEM image of the porous material for bone repair finally prepared in this example, which shows that the obtained porous fiber material has a fiber diameter of 300-500nm, uniform fiber diameter and smooth fiber surface, and 1-20 μm macropores are formed between fibers, and the porous structure is also easy for cell growth and adhesion.
The composite porous material for bone repair obtained in the embodiment has a tensile strength of 3.8MPa and cytotoxicity of 0 grade through detection, namely, has no cytotoxicity.
Example 2
A preparation method of a composite porous material for bone repair specifically comprises the following steps:
(1) measuring 10mL of ethyl orthosilicate, stirring and dissolving in 50mL of absolute ethyl alcohol to obtain solution A, measuring 50mL of ammonia water, stirring and dissolving in 100mL of absolute ethyl alcohol to obtain solution B;
(2) stirring the solution B at the speed of 150r/min under the condition of a water bath at the temperature of 50 ℃, dropwise adding the solution A into the solution B at the dropping speed of 1mL/min by a constant flow pump, wherein the volume ratio of the solution A to the solution B is 1:2, and after the dropwise addition is finished, continuously stirring and reacting for 36 hours, wherein the stirring speed is 150r/min, so as to obtain silicon dioxide sol which is marked as solution C;
(3) weighing 4g of hydroxyapatite whisker, ultrasonically dispersing in 10mL of absolute ethyl alcohol to prepare solution D, mixing the solution D and the solution C according to the volume ratio of 1:6, aging for 48h, filtering, drying for 24h at 50 ℃ in a forced air drying oven, and then sintering for 6h at 500 ℃ in an air atmosphere to obtain silicon dioxide modified hydroxyapatite whisker;
(4) dissolving 20g of gelatin in 100mL of glacial acetic acid at 60 ℃, and magnetically stirring for 4h at the speed of 150r/min to obtain a gelatin solution;
(5) adding 0.2g of the silicon dioxide modified hydroxyapatite whisker prepared in the step (3) into 100mL of the gelatin solution obtained in the step (4), magnetically stirring for 10 hours at the speed of 150r/min, and finally dispersing for 2 hours by using an ultrasonic machine to obtain a spinning stock solution;
(6) and (2) adopting a 16-gauge needle, setting the positive voltage to be 18KV, the negative voltage to be-3.5 KV, setting the injection speed of the spinning solution to be 0.15mm/min, setting the distance between the needle and a receiving device to be 20cm, connecting the positive electrode of a power supply to the needle, connecting the negative electrode of the power supply to a steel plate, carrying out electrostatic spinning on the spinning solution obtained in the step (5) to obtain spinning fibers, and crosslinking the spinning fibers for 30h by adopting a mixture of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxy sulphosuccinimide (EDC/NHS) in a mass ratio of 6:1 to obtain the composite porous material for bone repair.
FIG. 3 is an SEM image of the porous material for bone repair finally prepared in this example, which shows that the obtained porous fiber material has uniform fiber diameter of 250-350nm, smooth fiber surface, and 1-20 μm macropores formed between fibers, and the porous structure is also easy for cell growth and adhesion.
The composite porous material for bone repair obtained in the embodiment has a tensile strength of 4.0MPa, and has cytotoxicity of 0 grade through detection, namely, has no cytotoxicity.
Example 3
A preparation method of a composite porous material for bone repair specifically comprises the following steps:
(1) measuring 10mL of ethyl orthosilicate, stirring and dissolving in 80mL of absolute ethyl alcohol to obtain solution A, measuring 40mL of ammonia water, stirring and dissolving in 60mL of absolute ethyl alcohol to obtain solution B;
(2) stirring the solution B at the speed of 200r/min under the condition of a water bath at the temperature of 45 ℃, dropwise adding the solution A into the solution B at the dropping speed of 0.8mL/min by a constant flow pump, wherein the volume ratio of the solution A to the solution B is 1:1.5, and after the dropwise adding is finished, continuously stirring and reacting for 48 hours at the stirring speed of 200r/min to obtain silicon dioxide sol which is marked as solution C;
(3) weighing 5g of hydroxyapatite whisker, ultrasonically dispersing the hydroxyapatite whisker in 10mL of absolute ethyl alcohol to prepare solution D, mixing the solution D and the solution C according to the volume ratio of 1:10, aging for 72h, filtering, drying for 24h at 60 ℃ in a forced air drying oven, and sintering for 12h at 500 ℃ in an air atmosphere to obtain silicon dioxide modified hydroxyapatite whisker;
(4) dissolving 15g of gelatin in 100mL of glacial acetic acid at 90 ℃, and magnetically stirring for 5 hours at the speed of 100r/min to obtain a gelatin solution;
(5) adding 0.5g of the silicon dioxide modified hydroxyapatite whisker prepared in the step (3) into 100mL of the gelatin solution obtained in the step (4), magnetically stirring for 12 hours at the speed of 200r/min, and finally dispersing for 3 hours by using an ultrasonic machine to obtain a spinning stock solution;
(6) and (3) adopting a No. 17 needle, setting the positive voltage to be 20KV, the negative voltage to be-3.5 KV, setting the injection speed of the spinning solution to be 0.2mm/min, setting the distance between the needle and a receiving device to be 25cm, connecting the positive electrode of a power supply with the needle, connecting the negative electrode with a steel plate, carrying out electrostatic spinning on the spinning solution obtained in the step (5) to obtain spinning fibers, and crosslinking the spinning fibers for 36h by adopting glutaraldehyde to obtain the composite porous material for bone repair.
FIG. 4 is an SEM image of the porous material for bone repair finally prepared in this example, which shows that the obtained porous fiber material has fiber diameter distribution of 200-400nm, uniform fiber diameter, smooth fiber surface, and 1-20 μm macropores formed between fibers, and the porous structure is also easy for cell growth and adhesion.
The composite porous material for bone repair obtained in this example had a tensile strength of 4.5MPa and a cytotoxicity of 0 grade, i.e., no cytotoxicity.
Claims (10)
1. The preparation method of the composite porous material for bone repair is characterized by comprising the following steps:
(1) mixing ethyl orthosilicate and absolute ethyl alcohol according to a volume ratio of 1: 5-10 to prepare a solution A, and mixing ammonia water and absolute ethyl alcohol according to a volume ratio of 1: 1-2 to prepare a solution B;
(2) stirring the solution B in a water bath at 40-50 ℃, dripping the solution A into the solution B, and after finishing dripping, continuously stirring and reacting to obtain silicon dioxide sol which is marked as solution C;
(3) mixing the hydroxyapatite whisker and absolute ethyl alcohol according to a mass volume ratio g: mL of 0.1-0.5: 1 to prepare a solution D, mixing the solution D and the solution C according to a volume ratio of 1: 5-10, aging, filtering, drying and sintering to obtain a silicon dioxide modified hydroxyapatite whisker;
(4) dissolving gelatin in glacial acetic acid at 40-90 ℃ according to the mass volume ratio g: mL of 10-20: 100 of the gelatin to the glacial acetic acid, and magnetically stirring for 3-5 h to obtain a gelatin solution;
(5) adding the silicon dioxide modified hydroxyapatite whiskers in the step (3) into the gelatin solution in the step (4), magnetically stirring for 6-12 hours, and finally ultrasonically dispersing for 1-3 hours to obtain a spinning stock solution;
(6) and (3) adopting a flat receiver, connecting the positive electrode of a power supply with the needle head, connecting the negative electrode with a steel plate, carrying out electrostatic spinning on the spinning solution obtained in the step (5) to obtain spinning fibers, and crosslinking the spinning fibers by using a crosslinking agent to obtain the porous material for bone repair.
2. The method for preparing the composite porous material for bone repair according to claim 1, wherein the stirring speed of the solution B in the step (2) is 100 to 200 r/min; the dropping speed of dropping the A liquid into the B liquid is 0.5-1 mL/min, wherein the volume ratio of the A liquid to the B liquid is 1: 1-2.
3. The preparation method of the composite porous material for bone repair according to claim 1, wherein after the dropwise addition in the step (2) is completed, the stirring reaction is continued for 24-48 h, and the stirring speed is 100-200 r/min.
4. The method for preparing a composite porous material for bone repair according to claim 1, wherein the aging time in the step (3) is 24 to 72 hours.
5. The method for preparing the composite porous material for bone repair according to claim 1, wherein the drying manner in the step (3) is vacuum or forced air drying, the drying temperature is 30-60 ℃, and the drying time is 24 hours.
6. The preparation method of the composite porous material for bone repair according to claim 1, wherein the sintering in the step (3) is air atmosphere sintering, the sintering temperature is 500 ℃, and the sintering time is 4-12 h.
7. The preparation method of the composite porous material for bone repair according to claim 1, wherein the mass-to-volume ratio g/mL of the silica-modified hydroxyapatite whiskers to the gelatin solution in the step (5) is 0.1-0.5: 100.
8. The method for preparing a composite porous material for bone repair according to claim 1, wherein the magnetic stirring speed in the steps (4) and (5) is 100 to 200 r/min.
9. The method for preparing a composite porous material for bone repair according to claim 1, wherein the electrospinning conditions in the step (6) are as follows: the number of the used needle is 15-17, the advancing speed of the spinning solution is 0.1-0.2 mm/min, the positive voltage is 16-20 KV, the negative voltage is-3.5 KV, and the distance between the needle and the receiving device is 15-25 cm.
10. The method for preparing a composite porous material for bone repair according to claim 1, wherein the cross-linking agent in the step (6) is glutaraldehyde or a mixture of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and N-hydroxythiosuccinimide in a mass ratio of 6: 1; the crosslinking time is 24-36 h.
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