Magnetic hydrogel micro-spring as well as preparation method and application thereof

Abstract

The invention provides a magnetic hydrogel micro-spring as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: adding neogambogic acid and magnetic nanoparticles into a sodium alginate solution to prepare a magnetic mixed solution; adding calcium chloride into water to prepare a calcium chloride solution; building a micro-spring platform, wherein the micro-spring platform comprises a micro-fluid injection pump, an injector, a capillary tube, a calcium chloride tube, a first coil and a second coil; the magnetic mixed solution is injected into the injector, the calcium chloride solution is injected into the calcium chloride tube, the injector is pushed by the microfluid injection pump, the magnetic mixed solution is injected into the calcium chloride tube through the capillary tube, and the magnetic hydrogel micro-spring is formed under the action of the two-dimensional magnetic field coil. The prepared magnetic hydrogel micro-spring is good in sorting effect, so that the magnetic performance and the movement performance are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more particularly to magnetic hydrogel microsprings, preparation methods and applications thereof. Background Art

[0002] Gambogic acid has good inhibitory effects on a variety of tumors. However, due to the defects of poor water solubility, short half-life cycle, and strong vascular irritation of gambogic acid, its clinical application is greatly restricted. Loading gambogic acid with hydrogel can avoid the irritation of gambogic acid to blood vessels during transportation. At the same time, the slow release of gambogic acid can make up for the defect of the short half-life of gambogic acid. In order to better apply gambogic acid to clinical practice, some researchers use the emulsification evaporation method to prepare nanocapsules, and some researchers use 3D printing methods to prepare micro-nano capsules or micro-nano spheres to deliver gambogic acid. However, these preparation methods have the following disadvantages:

[0003] 1. High requirements for preparation conditions, complex equipment, and difficult to control the size of the drug delivery system.

[0004] 2. Poor motion performance of the drug delivery robot in human blood vessels, and unable to achieve controllable drug release.

[0005] Based on the above problems, researchers prepared calcium alginate hydrogel-based magnetic springs, which contain magnetically arranged Fe2O3 magnetic nanoparticles, making them responsive to magnetic fields. Under the action of a low-frequency rotating magnetic field, the springs are applied with torque to push them to move along the axis (Zheng D, Ramos-Sebastian A, Jung W S, et al. Fabrication and preliminary evaluation of alginate hydrogel-based magnetic springs with actively targeted heating and drug release mechanisms for cancer therapy[J]. Composites, Part B. Engineering, 2022(Feb.1):230.). However, the sorting effect of magnetic nanoparticles in this paper is poor, resulting in poor magnetic properties and motion performance. Summary of the Invention

[0006] Aiming at the above problems, the present invention provides magnetic hydrogel microsprings, preparation methods and applications thereof. The prepared magnetic hydrogel microsprings have good sorting effects, thereby improving magnetic properties and motion performance.

[0007] To achieve the object of the present invention, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a method for preparing magnetic hydrogel microsprings, comprising the following steps:

[0009] Add gambogic acid and magnetic nanoparticles to a sodium alginate solution to prepare a magnetic mixed solution; add calcium chloride to water to prepare a calcium chloride solution;

[0010] Set up a microspring platform, which includes a microfluidic injection pump, a syringe, a capillary tube, a calcium chloride tube, a first coil and a second coil. The microfluidic injection pump is connected to the syringe, one end of the capillary tube is connected to the syringe, and the other end of the capillary tube is connected to the calcium chloride tube; the first coil and the second coil are perpendicularly arranged to form a two-dimensional magnetic field coil, and the calcium chloride tube is arranged in the two-dimensional magnetic field coil;

[0011] Inject the magnetic mixed solution into the syringe, inject the calcium chloride solution into the calcium chloride tube, the microfluidic injection pump pushes the syringe, and the magnetic mixed solution is injected into the calcium chloride tube through the capillary tube. Under the action of the two-dimensional magnetic field coil, magnetic hydrogel microsprings are formed.

[0012] The following are preferred technical solutions of the present invention, but not limitations to the technical solutions provided by the present invention. Through the following technical solutions, the technical objectives and beneficial effects of the present invention can be better achieved and realized.

[0013] As a preferred technical solution of the present invention, the mass fraction of sodium alginate in the sodium alginate solution is 0.5%-2%. For example, 0.5%, 1%, 1.5%, 2.0%, etc., but not limited to the listed values. Other unlisted values within the above value range are equally applicable.

[0014] As a preferred technical solution of the present invention, the injection speed of the microfluidic injection pump is 1-5 ml / min. For example, 1 ml / min, 2 ml / min, 3 ml / min, 4 ml / min, 5 ml / min, etc., but not limited to the listed values. Other unlisted values within the above value range are equally applicable.

[0015] As a preferred technical solution of the present invention, the inner diameter of the capillary tube is 0.3-0.5 mm. For example, 0.3 mm, 0.4 mm, 0.5 mm, etc., but not limited to the listed values. Other unlisted values within the above value range are equally applicable.

[0016] As a preferred technical solution of the present invention, the magnetic nanoparticles are Fe2O3 particles.

[0017] As a preferred technical solution of the present invention, both the first coil and the second coil are Helmholtz coils. The first coil is arranged along the x-axis direction, and the second coil is arranged along the y-axis direction.

[0018] As a preferred technical solution of the present invention, the mass concentration of gambogic acid in the sodium alginate solution is 1% - 20%, such as 1%, 5%, 10%, 15%, 20%, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable.

[0019] The mass concentration of magnetic nanoparticles in the mixture of sodium alginate solution and gambogic acid is 10% - 20%, such as 10%, 15%, 20%, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable.

[0020] As a preferred technical solution of the present invention, the concentration of calcium chloride in the calcium chloride solution is 0.5% - 2%, such as 0.5%, 1%, 1.5%, 2%, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable.

[0021] In a second aspect, the present invention provides a magnetic hydrogel microspring prepared by the above preparation method.

[0022] In a third aspect, the present invention provides an application of the above magnetic hydrogel microspring, and the application includes being used for preparing a targeted drug delivery system and an auxiliary magnetic hyperthermia system.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] In the present invention, gambogic acid, magnetic nanoparticles and sodium alginate solution are mixed to obtain a magnetic mixed solution, which is added to a syringe, and then the calcium chloride solution is added to a calcium chloride tube. Under the action of a magnetic field, the magnetic mixed solution is injected into the calcium chloride tube, and the internal magnetic nanoparticles (MNP) are sorted throughout the process of spring formation, which can enhance the magnetic properties and magnetic thermal properties of the magnetic hydrogel microspring and improve the motion performance of the magnetic microspring.

[0025] The present invention uses microfluidic technology to prepare magnetic hydrogel microsprings, which can increase the drug loading capacity and achieve directional movement and controlled release of drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic structural diagram of the microspring platform provided by the present invention;

[0027] Figure 2 It is a perspective view of the microspring platform provided by the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0028] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0029] The present invention provides a preparation method of magnetic hydrogel microsprings, including the following steps:

[0030] Adding gambogic acid and magnetic nanoparticles (MNP) into a sodium alginate solution to prepare a magnetic mixed solution; adding calcium chloride into water to prepare a calcium chloride solution;

[0031] Constructing a microspring platform, the microspring platform includes a microfluidic injection pump 1, a syringe 2, a capillary 3, a calcium chloride tube 5, a first coil 6 and a second coil 7. The microfluidic injection pump is communicated with the syringe. One end of the capillary 3 is communicated with the syringe 2, and the other end of the capillary 3 is communicated with the calcium chloride tube 5; the first coil and the second coil are vertically arranged to form a two-dimensional magnetic field coil, and the calcium chloride tube 5 is arranged in the two-dimensional magnetic field coil;

[0032] Injecting the magnetic mixed solution into the syringe 2, injecting the calcium chloride solution into the calcium chloride tube 5, the microfluidic injection pump 1 pushes the syringe 2, and the magnetic mixed solution is injected into the calcium chloride tube 5 through the capillary 3. Under the action of the two-dimensional magnetic field coil, magnetic anisotropic hydrogel microsprings are formed.

[0033] Turn on the microfluidic microfluidic injection pump 1, and push the magnetic mixed solution in the syringe 2 to be injected into the calcium chloride tube 5 filled with the calcium chloride solution through the capillary 3. Sodium alginate reacts with calcium chloride, and Ca 2+ ions replace Na + ions, and the outer alginate solution crosslinks into a three-dimensional network hydrogel from the outside to the inside, and the volume changes to form magnetic hydrogel microsprings.

[0034] The magnetic nanoparticles in the hydrogel are linearly arranged along the magnetic field direction under the action of a static magnetic field, forming magnetic anisotropy, and enhancing the magnetic properties and magnetothermal properties of the hydrogel. In the present invention, MNP is arranged along the diameter direction of the spring throughout the gelation process of the hydrogel microspring, so that the magnetic hydrogel microspring has better magnetothermal conversion efficiency and motion performance. The specific method is as follows: First, control the injection speed of the microfluidic injection pump 1 so that the hydrogel microspring rotates around the axis of the spring at an angular velocity ω during the formation process. Then control the current I of the first coil 6 (Helmholtz coil) in the X-axis direction x= Icos(ωt) and the current I of the second coil 7 (Helmholtz coil) in the Y-axis direction y = Isin(ωt), where t is time and I is the current modulus. According to M = KI, where M is the magnetic field strength and K is the proportionality coefficient, a uniform magnetic field that rotates around the axis of the spring at an angular velocity ω can be generated, causing the magnetic nanoparticles in the magnetic hydrogel microspring to align along the diameter direction during the gelling process and be fixed in the hydrogel network.

[0035] The mass fraction of sodium alginate in the sodium alginate solution is 0.5% - 2%. Changing the concentration of sodium alginate in the sodium alginate solution (0.5% - 2%) can change the diameter of the microspring and the diameter of the spring wire, where the diameter of the microspring and the diameter of the spring wire increase as the concentration of sodium alginate decreases.

[0036] The injection speed of the microfluidic injection pump 1 is 1 - 5 ml / min. The microfluidic injection pump 1 used in the present invention is SPLAB02. Controlling the injection speed of the microfluidic injection pump 1 (1 - 5 ml / min) can regulate the pitch of the microspring, where the pitch of the microspring decreases as the injection speed of the microfluidic injection pump 1 increases.

[0037] The inner diameter of the capillary 3 is 0.3 - 0.5 mm. Changing the inner diameter of the capillary 3 can adjust the diameter of the microspring and the diameter of the spring wire, where the diameter of the microspring and the diameter of the spring wire increase as the inner diameter of the capillary 3 expands;

[0038] The magnetic nanoparticles are Fe2O3 particles.

[0039] The mass concentration of gambogic acid in the sodium alginate solution is 1% - 20%, and the mass concentration of magnetic nanoparticles in the mixture of sodium alginate solution and gambogic acid is 10% - 20%.

[0040] The concentration of calcium chloride in the calcium chloride solution is 0.5 - 2%. It should be noted that during the experiment, the volume of the calcium chloride solution in the test tube is relatively large, so there is no proportional requirement between raw materials such as calcium chloride and sodium alginate during the preparation process.

[0041] The present invention prepares a magnetic hydrogel microspring that can be used as a targeted drug delivery robot, loaded with gambogic acid, and can be applied to targeted drug delivery systems and auxiliary magnetic hyperthermia systems.

[0042] Specifically, injecting the magnetic hydrogel microsprings loaded with gambogic acid into the blood vessels as a targeted drug delivery robot can avoid the direct contact between gambogic acid and blood vessels and reduce the irritation of gambogic acid to blood vessels. Driven by a rotating magnetic field, the magnetic hydrogel microsprings can move to the targeted position directionally, slowly release the drug, and ensure the drug concentration in the targeted area for a long time. Under the action of an alternating magnetic field, the magnetic hydrogel microsprings will accelerate the release of gambogic acid to achieve a sudden release of the drug. At the same time, the temperature of the environment around the microsprings will be raised above 42 °C to kill cancer cells, achieving the purpose of assisting magnetic hyperthermia. The entire hydrogel microsprings can be biodegradable and non-toxic to the human body.

[0043] It should be noted that the drug loaded in the present invention is gambogic acid, and other drugs can also be used according to the usage requirements.

[0044] Example 1

[0045] Step 1: Put sodium alginate (NaAlg) and deionized water into a beaker at a mass ratio of 2:100, and stir with a magnetic stirrer for 60 minutes to fully dissolve NaAlg to form a sodium alginate solution.

[0046] Step 2: Mix gambogic acid and the sodium alginate solution at a volume ratio of 20:100, and stir with a magnetic stirrer for 30 minutes to make them fully mixed to obtain a mixed solution of sodium alginate and gambogic acid.

[0047] Step 3: Select 5 nm Fe2O3 particles as the MNP particles of the present invention. Add MNP to the mixed solution of sodium alginate and gambogic acid at a mass ratio of 1:10, and use an ultrasonic disperser to uniformly disperse MNP in the mixed solution. During the dispersion process, the temperature of the solution needs to be controlled below 25 °C, and disperse for 30 minutes to form a magnetic mixed solution. Use a vacuum degasser to remove the bubbles in the magnetic mixed solution and set it aside.

[0048] Step 4: Put calcium chloride (CaCl2) and deionized water into a beaker at a mass ratio of 2:100, and stir with a magnetic stirrer for 30 minutes to fully dissolve CaCl2 to form a calcium chloride solution and set it aside.

[0049] Step 5: Set up the test bench. As Figure 1 and Figure 2As shown, the magnetic mixed solution is filled in the syringe 2, the syringe 2 is installed on the microfluidic injection pump 1, one end of the capillary 3 is communicated with the syringe, and the other end of the capillary 3 is placed in the calcium chloride tube 5 filled with calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil composed of the first coil 6 (Helmholtz coil in the X-axis direction) and the second coil 7 (Helmholtz coil in the Y-axis direction). In this embodiment, there is no specific requirement for the coil current, and it is required that the magnetic field intensity generated by the coil is 10 mT.

[0050] Step 6: Control of microfluidics and formation of hydrogel microsprings.

[0051] Turn on the microfluidic injection pump 1, the injection speed of the microfluidic injection pump 1 is 1 ml / min, and push the magnetic mixed solution in the syringe 2 to be injected into the calcium chloride tube 5 filled with calcium chloride solution through the capillary 3 (the diameter of the capillary 3 is 0.3 mm). Sodium alginate reacts with calcium chloride, and Ca 2+ ions replace Na + ions, and the outer alginate solution crosslinks from the outside to the inside into a three-dimensional network hydrogel, and the volume changes to form magnetic calcium alginate hydrogel microsprings.

[0052] The pitch of the magnetic calcium alginate hydrogel microspring 4 prepared by the present invention is 0.4 mm. The diameter of the microspring is 0.7 mm.

[0053] The drug loading capacity of the magnetic calcium alginate hydrogel microspring 4 prepared by the present invention is 10%.

[0054] Example 2

[0055] Step 1: Put sodium alginate (NaAlg) and deionized water into a beaker according to a mass ratio of 2:100, and use a magnetic stirrer to stir for 60 minutes to fully dissolve NaAlg to form a sodium alginate solution.

[0056] Step 2: Mix gambogic acid and sodium alginate solution at a volume ratio of 20:100, and use a magnetic stirrer to stir for 30 minutes to make them fully mixed to obtain a mixed solution of sodium alginate and gambogic acid.

[0057] Step 3: Select 5 nm Fe2O3 particles as the MNP particles of the present invention. Add MNP to the mixed solution of sodium alginate and gambogic acid according to a mass ratio of 1:10, and use an ultrasonic disperser to uniformly disperse MNP into the mixed solution. During the dispersion process, the temperature of the solution needs to be controlled below 25 °C, and disperse for 30 minutes to form a magnetic mixed solution. Use a vacuum degasser to remove the bubbles in the solution, and set aside.

[0058] Step 4: Put calcium chloride (CaCl2) and deionized water into a beaker at a mass ratio of 2:100, and use a magnetic stirrer to stir for 30 minutes to fully dissolve CaCl2, forming a calcium chloride solution for standby.

[0059] Step 5: Set up the test bench. As Figure 1 and Figure 2 shown, the magnetic mixed solution is filled in the syringe 2, the syringe 2 is installed on the microfluidic injection pump 1, one end of the capillary 3 is communicated with the syringe, and the other end of the capillary 3 is placed in the calcium chloride tube 5 filled with the calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil composed of the first coil 6 (Helmholtz coil in the X-axis direction) and the second coil 7 (Helmholtz coil in the Y-axis direction). In this embodiment, there is no specific requirement for the coil current, and it is required that the magnetic field intensity generated by the coil is 10 mT.

[0060] Step 6: Control of microfluidics and formation of hydrogel microsprings.

[0061] Turn on the microfluidic injection pump 1, and the injection speed of the microfluidic injection pump 1 is 5 ml / min. Push the magnetic mixed solution in the syringe 2 to be injected into the calcium chloride tube 5 filled with the calcium chloride solution through the capillary 3 (the diameter of the capillary 3 is 0.3 mm). Sodium alginate reacts with calcium chloride, and Ca 2+ ions replace Na + ions, and the outer alginate solution crosslinks from the outside to the inside into a three-dimensional network hydrogel, and the volume changes, forming a magnetic calcium alginate hydrogel microspring.

[0062] The pitch of the magnetic calcium alginate hydrogel microspring 4 prepared by the present invention is 3 mm.

[0063] Example 3

[0064] Step 1: Put sodium alginate (NaAlg) and deionized water into a beaker at a mass ratio of 2:100, and use a magnetic stirrer to stir for 60 minutes to fully dissolve NaAlg, forming a sodium alginate solution.

[0065] Step 2: Mix gambogic acid and the sodium alginate solution at a volume ratio of 20:100, and use a magnetic stirrer to stir for 30 minutes to make them fully mixed to obtain a mixed solution of sodium alginate and gambogic acid.

[0066] Step 3: Select 5-nm Fe2O3 particles as the MNP particles of the present invention. Add MNP to the mixed solution of sodium alginate and gambogic acid according to a mass ratio of 1:10, and use an ultrasonic disperser to uniformly disperse MNP in the mixed solution. During the dispersion process, the temperature of the solution needs to be controlled below 25°C, and disperse for 30 minutes to form a magnetic mixed solution. Remove the bubbles in the magnetic mixed solution using a vacuum degasser and set it aside.

[0067] Step 4: Put calcium chloride (CaCl2) and deionized water into a beaker according to a mass ratio of 2:100, and use a magnetic stirrer to stir for 30 minutes to fully dissolve CaCl2 to form a calcium chloride solution, and set it aside.

[0068] Step 5: Set up the test bench. As Figure 1 and Figure 2 shown, load the magnetic mixed solution into the syringe 2, install the syringe 2 on the microfluidic injection pump 1, connect one end of the capillary 3 to the syringe, and place the other end of the capillary 3 in the calcium chloride tube 5 containing the calcium chloride solution. The calcium chloride tube 5 is installed in the two-dimensional magnetic field coil composed of the first coil 6 (Helmholtz coil in the X-axis direction) and the second coil 7 (Helmholtz coil in the Y-axis direction). In this embodiment, there is no specific requirement for the coil current, and it is required that the magnetic field intensity generated by the coil is 10 mT.

[0069] Step 6: Control of microfluidics and formation of hydrogel microsprings.

[0070] Open the microfluidic injection pump 1, and the injection speed of the microfluidic injection pump 1 is 5 ml / min. Push the magnetic mixed solution in the syringe 2 to be injected into the calcium chloride tube 5 containing the calcium chloride solution through the capillary 3 (the diameter of the capillary 3 is 0.3 mm). Sodium alginate reacts with calcium chloride, and Ca 2+ ions replace Na + ions, and the outer sodium alginate solution crosslinks into a three-dimensional network hydrogel from the outside to the inside, and the volume changes to form magnetic calcium alginate hydrogel microsprings.

[0071] The pitch of the magnetic calcium alginate hydrogel microspring 4 prepared by the present invention is 3 mm.

[0072] Example 4

[0073] Step 1: Put sodium alginate (NaAlg) and deionized water into a beaker according to a mass ratio of 2:100, and use a magnetic stirrer to stir for 60 minutes to fully dissolve NaAlg to form a sodium alginate solution.

[0074] Step 2: Mix gambogic acid with sodium alginate solution at a volume ratio of 20:100, and stir for 30 minutes using a magnetic stirrer to obtain a completely mixed solution of sodium alginate and gambogic acid.

[0075] Step 3: Select 5nm Fe2O3 particles as the MNP particles of the present invention. Add MNP to the mixed solution of sodium alginate and gambogic acid at a mass ratio of 1:10, and use an ultrasonic disperser to uniformly disperse MNP in the mixed solution. During the dispersion process, the temperature of the solution needs to be controlled below 25°C, and disperse for 30 minutes to form a magnetic mixed solution. Remove the bubbles in the solution of the magnetic mixed solution using a vacuum degasser and set aside.

[0076] Step 4: Put calcium chloride (CaCl2) and deionized water into a beaker at a mass ratio of 2:100, and stir for 30 minutes using a magnetic stirrer to fully dissolve CaCl2 to form a calcium chloride solution and set aside.

[0077] Step 5: Set up the test bench. As Figure 1 and Figure 2 shown, load the magnetic mixed solution into the syringe 2, install the syringe 2 on the microfluidic injection pump 1, connect one end of the capillary 3 to the syringe, and place the other end of the capillary 3 in the calcium chloride tube 5 containing the calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil composed of the first coil 6 (Helmholtz coil in the X-axis direction) and the second coil 7 (Helmholtz coil in the Y-axis direction). In this embodiment, there is no clear requirement for the coil current, and it is required that the magnetic field intensity generated by the coil is 10mT.

[0078] Step 6: Control of microfluidics and formation of hydrogel microsprings.

[0079] Open the microfluidic injection pump 1, the injection speed of the microfluidic injection pump 1 is 1ml / min, and push the magnetic mixed solution in the syringe 2 to be injected into the calcium chloride tube 5 containing the calcium chloride solution through the capillary 3 (the diameter of the capillary 3 is 0.5mm). Sodium alginate reacts with calcium chloride, and Ca 2+ ions replace Na + ions, and the outer sodium alginate solution crosslinks into a three-dimensional network hydrogel from the outside to the inside, and the volume changes to form magnetic calcium alginate hydrogel microsprings.

[0080] The diameter of the magnetic calcium alginate hydrogel microspring 4 prepared by the present invention is 2mm.

[0081] Example 5

[0082] Step 1: Sodium alginate (NaAlg) and deionized water are put into a beaker at a mass ratio of 0.5:100, and a magnetic stirrer is used to stir for 60 minutes to fully dissolve NaAlg, forming a sodium alginate solution.

[0083] Step 2: Neo-gambogic acid and the sodium alginate solution are mixed at a volume ratio of 1:100, and a magnetic stirrer is used to stir for 30 minutes to fully mix them, obtaining a mixed solution of sodium alginate and neo-gambogic acid.

[0084] Step 3: 5-nm Fe2O3 particles are selected as the MNP particles of the present invention. According to a mass ratio of 2:10, MNP is added to the mixed solution of sodium alginate and neo-gambogic acid, and an ultrasonic disperser is used to uniformly disperse MNP in the mixed solution. During the dispersion process, the temperature of the solution needs to be controlled below 25°C, and it is dispersed for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution is defoamed by a vacuum defoamer to remove the bubbles in the solution and is reserved.

[0085] Step 4: Calcium chloride (CaCl2) and deionized water are put into a beaker at a mass ratio of 0.5:100, and a magnetic stirrer is used to stir for 30 minutes to fully dissolve CaCl2, forming a calcium chloride solution and reserving it.

[0086] Step 5: Setup of the test bench. As Figure 1 and Figure 2 shown, the magnetic mixed solution is filled in the syringe 2, the syringe 2 is installed on the microfluidic injection pump 1, one end of the capillary 3 is communicated with the syringe, and the other end of the capillary 3 is placed in the calcium chloride tube 5 filled with the calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil composed of the first coil 6 (Helmholtz coil in the X-axis direction) and the second coil 7 (Helmholtz coil in the Y-axis direction). In this embodiment, there is no specific requirement for the coil current, and it is required that the magnetic field intensity generated by the coil is 10 mT.

[0087] Step 6: Control of microfluidics and formation of hydrogel microsprings.

[0088] The microfluidic injection pump 1 is turned on, and the injection speed of the microfluidic injection pump 1 is 1 ml / min. The magnetic mixed solution in the syringe 2 is pushed by the microfluidic injection pump 1 to be injected into the calcium chloride tube 5 filled with the calcium chloride solution through the capillary 3 (the diameter of the capillary 3 is 0.3 mm). Sodium alginate reacts with calcium chloride, and Ca 2+ ions replace Na + ions, and the outer alginate solution crosslinks from the outside to the inside into a three-dimensional network hydrogel, and the volume changes, forming magnetic calcium alginate hydrogel microsprings.

[0089] Example 6

[0090] Step 1: Sodium alginate (NaAlg) and deionized water are put into a beaker at a mass ratio of 1:100, and a magnetic stirrer is used to stir for 60 minutes to fully dissolve NaAlg and form a sodium alginate solution.

[0091] Step 2: Neo-gambogic acid and the sodium alginate solution are mixed at a volume ratio of 10:100, and a magnetic stirrer is used to stir for 30 minutes to completely mix them to obtain a mixed solution of sodium alginate and neo-gambogic acid.

[0092] Step 3: 5 nm Fe2O3 particles are selected as the MNP particles of the present invention. MNP is added to the mixed solution of sodium alginate and neo-gambogic acid at a mass ratio of 5:10, and an ultrasonic disperser is used to uniformly disperse MNP into the mixed solution. During the dispersion process, the temperature of the solution needs to be controlled below 25 °C, and disperse for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution is deaerated by a vacuum deaerator to remove the bubbles in the solution and set aside.

[0093] Step 4: Calcium chloride (CaCl2) and deionized water are put into a beaker at a mass ratio of 1:100, and a magnetic stirrer is used to stir for 30 minutes to fully dissolve CaCl2 and form a calcium chloride solution for standby.

[0094] Step 5: Setup of the test bench. As Figure 1 and Figure 2 shown, the magnetic mixed solution is filled in the syringe 2, the syringe 2 is installed on the microfluidic injection pump 1, one end of the capillary 3 is communicated with the syringe, and the other end of the capillary 3 is placed in the calcium chloride tube 5 filled with the calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil composed of the first coil 6 (Helmholtz coil in the X-axis direction) and the second coil 7 (Helmholtz coil in the Y-axis direction). In this embodiment, there is no clear requirement for the coil current, and it is required that the magnetic field intensity generated by the coil is 10 mT.

[0095] Step 6: Control of microfluidics and formation of hydrogel microsprings.

[0096] Turn on the microfluidic injection pump 1, the injection speed of the microfluidic injection pump 1 is 3 ml / min, and the magnetic mixed solution in the syringe 2 is pushed to be injected into the calcium chloride tube 5 filled with the calcium chloride solution through the capillary 3 (the diameter of the capillary 3 is 0.4 mm). Sodium alginate reacts with calcium chloride, and Ca 2+ ions replace Na + ions, and the outer alginate solution crosslinks from the outside to the inside into a three-dimensional network hydrogel, and the volume changes to form magnetic calcium alginate hydrogel microsprings.

[0097] Comparative Example 1

[0098] It was prepared by referring to the paper (Zheng D, Ramos-Sebastian A, Jung W S, et al. Fabrication and preliminary evaluation of alginate hydrogel-based magnetic springs with actively targeted heating and drug release mechanisms for cancer therapy[J]. Composites, Part B. Engineering, 2022(Feb.1):230.), and the preparation steps are as follows:

[0099] 2 g of NaAlg was added to 100 ml of deionized water and stirred for 90 min. Then, Fe2O3 was added to the sodium alginate solution at a mass concentration of 10%. After ultrasonic dispersion for 60 min, a mixed solution was obtained.

[0100] 2 g of CaCl2 was added to 100 ml of deionized water and magnetically stirred for 10 min to completely dissolve CaCl2. The mixed solution was added to a 5-ml syringe. Then, the capillary was processed into the required bevel angle and connected to the syringe. The tip of the capillary was immersed in the CaCl2 solution. The mixed solution was injected into the CaCl2 solution at a rate of 1.2 mL / min to initiate a crosslinking reaction, forming a hydrogel in the shape of a spring. Then, a magnetic field intensity of 25 mT was vertically applied to the diameter direction of the spring-shaped hydrogel for 15 min to obtain the required microspring.

[0101] The products prepared in Example 1 with a MNP mass concentration of 10% and Comparative Example 1 were heated under an alternating magnetic field with a current of 15 kA / m and a frequency of 200 kHz for 5 minutes. The temperature of the microspring prepared by the method of Comparative Example 1 was 38.3 °C, while the temperature of the magnetic calcium alginate hydrogel microspring prepared in Example 1 reached 42.1 °C, and the temperature of the magnetic calcium alginate hydrogel microspring prepared in Example 2 reached 41.9 °C. Magnetic hyperthermia is a method of treating diseases by generating heat with magnetic nanoparticles under an alternating magnetic field. The temperature of the microspring prepared in the present invention can be increased to above 42 °C to kill cancer cells, achieving the purpose of assisting magnetic hyperthermia. This shows that the microspring prepared by the present invention has better magnetic thermal performance.

[0102] When the product prepared in Comparative Example 1 was under a rotating magnetic field with a strength of 4 mT and a rotating frequency of 5, the micro-spring lost steps, and the micro-spring could not rotate synchronously with the magnetic field. However, the magnetic calcium alginate hydrogel micro-springs prepared in Examples 1 - 6 still did not lose steps when the rotating magnetic field strength was 4 mT and the rotating frequency was 14, and still rotated synchronously with the magnetic field. Taking the magnetic calcium alginate hydrogel micro-spring prepared in Example 1 as an example, the linear moving speed of the micro-spring was about 4 mm / s. This proves that the micro-springs prepared by the present invention have better magnetic properties and motion performance.

[0103] In the preparation process of Comparative Example 1, calcium chloride was placed in a small square container. The injection pump was turned on. After the micro-spring was initially gelled and formed, the square container containing calcium chloride and the micro-spring was placed in a one-dimensional Helmholtz coil, and the coil power supply was turned on to generate a magnetic field to sort the MNPs in the micro-spring.

[0104] In the present invention, the test tube containing calcium chloride is placed in a two-dimensional Helmholtz coil. While starting the microfluidic injection pump, the coil current is turned on to generate a rotating magnetic field, and the MNPs inside are affected by the magnetic field to be sorted during the entire gelling process of the micro-spring formation.

[0105] The main advantages of the present invention include the following aspects:

[0106] 1. The integrated control of the injection pump and the magnetic field is more convenient than manually moving the micro-spring and separately controlling the injection pump and the magnetic field in Comparative Example 1, with a high degree of automation;

[0107] 2. The axis of the micro-spring prepared in Comparative Example 1 was in the horizontal direction during the formation process. Affected by its own gravity during the formation process, the micro-spring would bend and sink, affecting the motion performance of the micro-spring. However, the axis direction of the micro-spring prepared by the present invention is in the vertical direction, which can maintain the uniformity of the spring structure;

[0108] 3. In the present application, the MNPs in the micro-spring are sorted throughout the whole process of preparing the magnetic hydrogel micro-spring, while the method in Comparative Example 1 only sorts the MNPs after the spring is initially formed. The sorting effect of the MNPs in the present invention is better, making the magnetic properties, magnetothermal properties and motion performance of the micro-spring more excellent.

[0109] In the present invention, under the action of a static magnetic field, the magnetic nanoparticles (MNP) will rotate to align their magnetic moments with the direction of the external static magnetic field. Therefore, in the hydrogel containing MNP, the MNP in the hydrogel are arranged linearly along the magnetic field direction under the action of the static magnetic field, endowing the hydrogel with magnetic anisotropy. According to the calculation formula of magnetic torque and the mechanism of magnetic heat conversion, the hydrogel with magnetic anisotropy will generate a greater magnetic torque and calorific value under the action of a rotating magnetic field and a high-frequency alternating magnetic field. However, in Comparative Example 1, after the microspring is formed, the magnetic field is turned on to sort the MNP therein. At this time, most of the MNP have been fixed in position by the hydrogel and are difficult to rotate and move, resulting in a poor sorting effect. In the present invention, sorting starts at the beginning of the formation of the microspring and a fixed diameter direction is maintained to rotate synchronously with the microspring. Most of the MNP can move and rotate freely and are solidified by the hydrogel, enabling the MNP to maintain a good linear sorting state and having a better sorting effect. Therefore, the microspring prepared by the present invention has better magnetic anisotropy performance.

[0110] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications to these embodiments once they learn the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments and all changes and modifications falling within the scope of the present invention.

[0111] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A preparation method of a magnetic hydrogel microspring, characterized in that, It includes the following steps: Adding gambogic acid and magnetic nanoparticles into sodium alginate solution to prepare a magnetic mixed solution; adding calcium chloride into water to prepare a calcium chloride solution. Constructing a microspring platform, which includes a microfluidic injection pump (1), a syringe (2), a capillary tube (3), a calcium chloride tube (5), a first coil (6) and a second coil (7). The microfluidic injection pump (1) is communicated with the syringe (2). One end of the capillary tube (3) is communicated with the syringe (2), and the other end of the capillary tube (3) is communicated with the calcium chloride tube (5). The first coil (6) and the second coil (7) are vertically arranged to form a two-dimensional magnetic field coil, and the calcium chloride tube (5) is arranged in the two-dimensional magnetic field coil. Injecting the magnetic mixed solution into the syringe (2), injecting the calcium chloride solution into the calcium chloride tube (5). The microfluidic injection pump (1) pushes the syringe (2), and the magnetic mixed solution is injected into the calcium chloride tube (5) through the capillary tube (3). Under the action of the two-dimensional magnetic field coil, magnetic hydrogel microsprings are formed.

2. The preparation method of a magnetic hydrogel microspring according to claim 1, characterized in that, The mass fraction of sodium alginate in the sodium alginate solution is 0.5%-2%.

3. The preparation method of a magnetic hydrogel microspring according to claim 1, characterized in that, The injection speed of the microfluidic injection pump (1) is 1-5 ml / min.

4. The preparation method of a magnetic hydrogel microspring according to claim 1, wherein, The inner diameter of the capillary tube (3) is 0.3-0.5 mm.

5. The preparation method of a magnetic hydrogel microspring according to claim 1, characterized in that, The magnetic nanoparticles are Fe2O3 particles.

6. The preparation method of a magnetic hydrogel microspring according to claim 1, characterized in that, Both the first coil (6) and the second coil (7) are Helmholtz coils. The first coil (6) is arranged along the x-axis direction, and the second coil (7) is arranged along the y-axis direction.

7. The preparation method of a magnetic hydrogel microspring according to claim 2, characterized in that, The mass concentration of gambogic acid in the sodium alginate solution is 1%-20%, and the mass concentration of magnetic nanoparticles in the mixture of sodium alginate solution and gambogic acid is 10%-20%.

8. The preparation method of a magnetic hydrogel microspring according to claim 2, characterized in that, The concentration of calcium chloride in the calcium chloride solution is 0.5%-2%.

9. The magnetic hydrogel microsprings prepared by the preparation method according to any one of claims 1-8.

10. Application of the magnetic hydrogel microsprings according to claim 9 in preparing a targeted drug delivery system and an auxiliary magnetic hyperthermia system.

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