Magnetic hydrogel microspring and its preparation method and application

Abstract

The present invention provides a magnetic hydrogel microspring, preparation method, and application, belonging to the field of pharmaceutical preparation technology. The preparation method is as follows: neogambogic acid and magnetic nanoparticles are added to a sodium alginate solution to prepare a magnetic mixed solution; calcium chloride is added to water to prepare a calcium chloride solution; a microspring platform is constructed, comprising a microfluidic injection pump, a syringe, a capillary, a calcium chloride tube, a first coil, and a second coil; the magnetic mixed solution is injected into the syringe, and the calcium chloride solution is injected into the calcium chloride tube. The microfluidic injection pump propels the syringe, and the magnetic mixed solution is injected into the calcium chloride tube through the capillary. Under the action of the two-dimensional magnetic field coil, a magnetic hydrogel microspring is formed. The magnetic hydrogel microspring prepared by the present invention has a good sorting effect, thereby improving magnetic properties and motion performance.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more particularly to a magnetic hydrogel microspring and a preparation method and application thereof. Background Art

[0002] Neogamoic acid has a good inhibitory effect on various tumors, but its poor water solubility, short half-life, and strong vascular stimulation have greatly limited its clinical application. Using hydrogel to load neogamoic acid can avoid the stimulation of blood vessels by neogamoic acid during delivery. At the same time, the slow release of neogamoic acid can make up for the short half-life of neogamoic acid. In order to better apply neogamoic acid in clinical practice, some researchers use emulsification evaporation to prepare nanocapsules, and some researchers use 3D printing to prepare micro-nanocapsules or micro-nanospheres to deliver neogamoic acid. However, these preparation methods have the following disadvantages:

[0003] 1. The preparation conditions are demanding, the equipment is complex, and the size of the drug delivery system is difficult to control.

[0004] 2. The drug delivery robot has poor movement performance in human blood vessels and cannot achieve controlled drug release.

[0005] Based on the above problems, the researchers prepared calcium alginate hydrogel-based magnetic springs containing magnetically aligned Fe2O3 magnetic nanoparticles to make them responsive to magnetic fields. Under the action of a low-frequency rotating magnetic field, torque is applied to the springs, pushing them to move axially (Zheng D, Ramos-Sebastian A, Jung WS, 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 poor ordering of magnetic nanoparticles in this paper results in poor magnetic properties and motion performance. Summary of the Invention

[0006] In response to the above problems, the present invention provides a magnetic hydrogel microspring and its preparation method and application. The prepared magnetic hydrogel microspring has a good sorting effect, thereby improving the magnetic properties and motion performance.

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

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

[0009] Adding neogambogic acid and magnetic nanoparticles to a sodium alginate solution to prepare a magnetic mixed solution; adding calcium chloride to water to prepare a calcium chloride solution;

[0010] A microspring platform is constructed, comprising a microfluidic injection pump, a syringe, a capillary tube, a calcium chloride tube, a first coil, and a second coil, wherein 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 arranged perpendicularly to form a two-dimensional magnetic field coil, and the calcium chloride tube is disposed within the two-dimensional magnetic field coil;

[0011] The magnetic mixed solution is injected into the syringe, the calcium chloride solution is injected into the calcium chloride tube, the microfluidic injection pump pushes the syringe, the magnetic mixed solution is injected into the calcium chloride tube through the capillary, and under the action of the two-dimensional magnetic field coil, a magnetic hydrogel microspring is formed.

[0012] The following are preferred technical solutions of the present invention, but are not intended to limit 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%, such as 0.5%, 1%, 1.5%, 2.0%, etc., but is not limited to the listed values, and other values ​​not listed within the above numerical range are also 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 is not limited to the listed values. Other values ​​not listed within the above numerical range are also applicable.

[0015] As a preferred technical solution of the present invention, the inner diameter of the capillary is 0.3-0.5 mm, such as 0.3 mm, 0.4 mm, 0.5 mm, etc., but is not limited to the listed values. Other values ​​not listed within the above numerical range are also 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, the first coil and the second coil are both 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 neogambogic acid in the sodium alginate solution is 1%-20%, for example 1%, 5%, 10%, 15%, 20%, etc., but is not limited to the listed values, and other values ​​not listed within the above numerical range are also applicable.

[0019] The mass concentration of magnetic nanoparticles in the mixture of sodium alginate solution and neogambogic acid is 10%-20%, for example 10%, 15%, 20%, etc., but is not limited to the listed values. Other values ​​not listed within the above numerical range are also 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%, for example, 0.5%, 1%, 1.5%, 2%, etc., but is not limited to the listed values. Other values ​​not listed within the above numerical range are also 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 applications of the magnetic hydrogel microspring, including applications for preparing targeted drug delivery systems and auxiliary magnetic hyperthermia systems.

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

[0024] The present invention mixes neogamonic acid, magnetic nanoparticles and a sodium alginate solution to obtain a magnetic mixed solution, adds the mixed solution into a syringe, then adds a calcium chloride solution into a calcium chloride tube, and injects the magnetic mixed solution into the calcium chloride tube under the action of a magnetic field. During the entire process of spring formation, the internal magnetic nanoparticles (MNPs) are sorted, thereby enhancing the magnetic and magnetocaloric properties of the magnetic hydrogel microspring and improving the motion performance of the magnetic microspring.

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

[0026] Figure 1 A schematic structural diagram of the micro-spring platform provided by the present invention;

[0027] Figure 2 A three-dimensional diagram of the microspring platform provided by the present invention. DETAILED DESCRIPTION

[0028] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0029] The present invention provides a method for preparing a magnetic hydrogel microspring, comprising the following steps:

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

[0031] A microspring platform is constructed, comprising 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 is connected to the syringe, one end of the capillary tube 3 is connected to the syringe 2, and the other end of the capillary tube 3 is connected to the calcium chloride tube 5. The first coil and the second coil are arranged perpendicularly to form a two-dimensional magnetic field coil, and the calcium chloride tube 5 is disposed in the two-dimensional magnetic field coil.

[0032] The magnetic mixed solution is injected into the syringe 2, the calcium chloride solution is injected 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, a magnetic anisotropic hydrogel microspring is formed.

[0033] Turn on the microfluidic injection pump 1, push the magnetic mixed solution in the syringe 2 to be injected into the calcium chloride tube 5 containing calcium chloride solution through the capillary 3, and the sodium alginate reacts with the calcium chloride, Ca 2+ Ion replacement for Na + ions, the outer layer of alginate solution is cross-linked from the outside to the inside into a three-dimensional network of hydrogel, the volume changes, and a magnetic hydrogel microspring is formed.

[0034] Under the action of a static magnetic field, the magnetic nanoparticles in the hydrogel are linearly arranged along the direction of the magnetic field, forming magnetic anisotropy and enhancing the magnetic and magnetothermal properties of the hydrogel. The present invention arranges the MNPs along the diameter direction of the spring during the entire process of hydrogel microspring gelation, so that the magnetic hydrogel microspring has a better magnetothermal conversion rate and motion performance. The specific method is as follows: first, the injection speed of the microfluidic injection pump 1 is controlled so that the hydrogel microspring rotates around the axis of the spring at an angular velocity ω during the formation process. Then, the current I of the first coil 6 (Helmholtz coil) in the X-axis direction is controlled. 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 intensity and K is the proportional coefficient, a uniform magnetic field can be generated that rotates around the axis of the spring at an angular velocity ω, so that the magnetic nanoparticles in the magnetic hydrogel microspring are aligned along the diameter direction during the gelation process and fixed in the hydrogel grid.

[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. The diameter of the microspring and the diameter of the spring wire increase as the concentration of sodium alginate decreases.

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

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

[0038] The magnetic nanoparticles are Fe2O3 particles.

[0039] The mass concentration of the neogambogic acid in the sodium alginate solution is 1%-20%, and the mass concentration of the magnetic nanoparticles in the mixture of the sodium alginate solution and the neogambogic 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 ratio requirement between the raw materials such as calcium chloride and sodium alginate during the preparation process.

[0041] The present invention prepares a magnetic hydrogel microspring which can be used as a targeted drug delivery robot, is loaded with neogambogic acid, and can be applied to a targeted drug delivery system and an auxiliary magnetic hyperthermia system.

[0042] Specifically, magnetic hydrogel microsprings loaded with neogamonic acid are injected into blood vessels as a targeted drug delivery robot, which can prevent direct contact between neogamonic acid and blood vessels and reduce the stimulation of neogamonic acid on blood vessels. Driven by a rotating magnetic field, the magnetic hydrogel microspring can move directionally to the target position, slowly release the drug, and maintain the drug concentration in the targeted area for a long time. Under the action of the alternating magnetic field, the magnetic hydrogel microspring will accelerate the release of neogamonic acid, achieving a burst release of the drug, while simultaneously raising the temperature of the environment surrounding the microspring to above 42°C, killing cancer cells and achieving the purpose of auxiliary magnetic hyperthermia. The entire hydrogel microspring is biodegradable and non-toxic to the human body.

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

[0044] Example 1

[0045] Step 1: Sodium alginate (NaAlg) and deionized water are placed in a beaker at a mass ratio of 2:100 and stirred using a magnetic stirrer for 60 minutes to fully dissolve the NaAlg to form a sodium alginate solution.

[0046] Step 2: Mix the neogambogic acid and the sodium alginate solution in a volume ratio of 20:100, and stir them using a magnetic stirrer for 30 minutes to completely mix them to obtain a mixed solution of sodium alginate and neogambogic acid.

[0047] Step 3: 5 nm Fe2O3 particles were selected as the MNPs of the present invention. The MNPs were added to a mixed solution of sodium alginate and neogambogic acid at a mass ratio of 1:10. The MNPs were evenly dispersed into the mixed solution using an ultrasonic disperser. The solution temperature was maintained below 25°C during the dispersion process. The dispersion was continued for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution was then deaerated using a vacuum degasser and set aside.

[0048] Step 4: Place calcium chloride (CaCl2) and deionized water in a beaker at a mass ratio of 2:100, and stir using a magnetic stirrer for 30 minutes to fully dissolve the CaCl2 to form a calcium chloride solution for later use.

[0049] Step 5: Test bench construction. Figure 1 and Figure 2As shown, the magnetic mixed solution is contained in the syringe 2, and 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 containing calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil consisting of the first coil 6 (X-axis Helmholtz coil) and the second coil 7 (Y-axis Helmholtz coil). In this embodiment, there is no clear requirement for the coil current, and the magnetic field strength generated by the coil is required to be 10mT.

[0050] Step 6: Microfluidics control and hydrogel microspring formation.

[0051] The microfluidic injection pump 1 is turned on at an injection speed of 1 ml / min, pushing 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+ Ion replacement for Na + ions, the outer layer of alginate solution is cross-linked from the outside to the inside into a three-dimensional network of hydrogel, the volume changes, and a magnetic calcium alginate hydrogel microspring is formed.

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

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

[0054] Example 2

[0055] Step 1: Sodium alginate (NaAlg) and deionized water are placed in a beaker at a mass ratio of 2:100 and stirred using a magnetic stirrer for 60 minutes to fully dissolve the NaAlg to form a sodium alginate solution.

[0056] Step 2: Mix the neogambogic acid and the sodium alginate solution in a volume ratio of 20:100, and stir them using a magnetic stirrer for 30 minutes to completely mix them to obtain a mixed solution of sodium alginate and neogambogic acid.

[0057] Step 3: 5 nm Fe2O3 particles were selected as the MNPs of the present invention. The MNPs were added to a mixed solution of sodium alginate and neogambogic acid at a mass ratio of 1:10. The MNPs were evenly dispersed into the mixed solution using an ultrasonic disperser. The solution temperature was maintained below 25°C during the dispersion process. The dispersion was continued for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution was then deaerated using a vacuum degasser and set aside.

[0058] Step 4: Place calcium chloride (CaCl2) and deionized water in a beaker at a mass ratio of 2:100, and stir using a magnetic stirrer for 30 minutes to fully dissolve the CaCl2 to form a calcium chloride solution for later use.

[0059] Step 5: Test bench construction. Figure 1 and Figure 2 As shown, the magnetic mixed solution is contained in the syringe 2, and 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 containing calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil consisting of the first coil 6 (X-axis Helmholtz coil) and the second coil 7 (Y-axis Helmholtz coil). In this embodiment, there is no clear requirement for the coil current, and the magnetic field strength generated by the coil is required to be 10mT.

[0060] Step 6: Microfluidics control and hydrogel microspring formation.

[0061] The microfluidic injection pump 1 is turned on at an injection speed of 5 ml / min, pushing 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+ Ion replacement for Na + ions, the outer layer of alginate solution is cross-linked from the outside to the inside into a three-dimensional network of hydrogel, the volume changes, and a magnetic calcium alginate hydrogel microspring is formed.

[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: Sodium alginate (NaAlg) and deionized water are placed in a beaker at a mass ratio of 2:100 and stirred using a magnetic stirrer for 60 minutes to fully dissolve the NaAlg to form a sodium alginate solution.

[0065] Step 2: Mix the neogambogic acid and the sodium alginate solution in a volume ratio of 20:100, and stir them using a magnetic stirrer for 30 minutes to completely mix them to obtain a mixed solution of sodium alginate and neogambogic acid.

[0066] Step 3: 5 nm Fe2O3 particles were selected as the MNPs of the present invention. The MNPs were added to a mixed solution of sodium alginate and neogambogic acid at a mass ratio of 1:10. The MNPs were evenly dispersed into the mixed solution using an ultrasonic disperser. The solution temperature was maintained below 25°C during the dispersion process. The dispersion was continued for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution was then deaerated using a vacuum degasser and set aside.

[0067] Step 4: Place calcium chloride (CaCl2) and deionized water in a beaker at a mass ratio of 2:100, and stir using a magnetic stirrer for 30 minutes to fully dissolve the CaCl2 to form a calcium chloride solution for later use.

[0068] Step 5: Test bench construction. Figure 1 and Figure 2 As shown, the magnetic mixed solution is contained in the syringe 2, and 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 containing calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil consisting of the first coil 6 (X-axis Helmholtz coil) and the second coil 7 (Y-axis Helmholtz coil). In this embodiment, there is no clear requirement for the coil current, and the magnetic field strength generated by the coil is required to be 10mT.

[0069] Step 6: Microfluidics control and hydrogel microspring formation.

[0070] The microfluidic injection pump 1 is turned on at an injection speed of 5 ml / min, pushing 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+ Ion replacement for Na + ions, the outer layer of alginate solution is cross-linked from the outside to the inside into a three-dimensional network of hydrogel, the volume changes, and a magnetic calcium alginate hydrogel microspring is formed.

[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: Sodium alginate (NaAlg) and deionized water are placed in a beaker at a mass ratio of 2:100 and stirred using a magnetic stirrer for 60 minutes to fully dissolve the NaAlg to form a sodium alginate solution.

[0074] Step 2: Mix the neogambogic acid and the sodium alginate solution in a volume ratio of 20:100, and stir them using a magnetic stirrer for 30 minutes to completely mix them to obtain a mixed solution of sodium alginate and neogambogic acid.

[0075] Step 3: 5 nm Fe2O3 particles were selected as the MNPs of the present invention. The MNPs were added to a mixed solution of sodium alginate and neogambogic acid at a mass ratio of 1:10. The MNPs were evenly dispersed into the mixed solution using an ultrasonic disperser. The solution temperature was maintained below 25°C during the dispersion process. The dispersion was continued for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution was then deaerated using a vacuum degasser and set aside.

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

[0077] Step 5: Test bench construction. Figure 1 and Figure 2 As shown, the magnetic mixed solution is contained in the syringe 2, and 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 containing calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil consisting of the first coil 6 (X-axis Helmholtz coil) and the second coil 7 (Y-axis Helmholtz coil). In this embodiment, there is no clear requirement for the coil current, and the magnetic field strength generated by the coil is required to be 10mT.

[0078] Step 6: Microfluidics control and hydrogel microspring formation.

[0079] The microfluidic injection pump 1 is turned on at an injection speed of 1 ml / min, pushing 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 0.5 mm). Sodium alginate reacts with calcium chloride, and Ca 2+ Ion replacement for Na + ions, the outer layer of alginate solution is cross-linked from the outside to the inside into a three-dimensional network of hydrogel, the volume changes, and a magnetic calcium alginate hydrogel microspring is formed.

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

[0081] Example 5

[0082] Step 1: Sodium alginate (NaAlg) and deionized water are placed in a beaker at a mass ratio of 0.5:100 and stirred using a magnetic stirrer for 60 minutes to fully dissolve the NaAlg to form a sodium alginate solution.

[0083] Step 2: Mix the neogambogic acid and the sodium alginate solution in a volume ratio of 1:100, and stir them using a magnetic stirrer for 30 minutes to completely mix them to obtain a mixed solution of sodium alginate and neogambogic acid.

[0084] Step 3: 5 nm Fe2O3 particles were selected as the MNPs of the present invention. The MNPs were added to a mixed solution of sodium alginate and neogambogic acid at a mass ratio of 2:10. The MNPs were evenly dispersed into the mixed solution using an ultrasonic disperser. The solution temperature was maintained below 25°C during the dispersion process. The dispersion was continued for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution was then deaerated using a vacuum degasser and set aside.

[0085] Step 4: Place calcium chloride (CaCl2) and deionized water in a beaker at a mass ratio of 0.5:100, and stir using a magnetic stirrer for 30 minutes to fully dissolve the CaCl2 to form a calcium chloride solution for later use.

[0086] Step 5: Test bench construction. Figure 1 and Figure 2 As shown, the magnetic mixed solution is contained in the syringe 2, and 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 containing calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil consisting of the first coil 6 (X-axis Helmholtz coil) and the second coil 7 (Y-axis Helmholtz coil). In this embodiment, there is no clear requirement for the coil current, and the magnetic field strength generated by the coil is required to be 10mT.

[0087] Step 6: Microfluidics control and hydrogel microspring formation.

[0088] The microfluidic injection pump 1 is turned on at an injection speed of 1 ml / min, pushing 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+ Ion replacement for Na + ions, the outer layer of alginate solution is cross-linked from the outside to the inside into a three-dimensional network of hydrogel, the volume changes, and a magnetic calcium alginate hydrogel microspring is formed.

[0089] Example 6

[0090] Step 1: Sodium alginate (NaAlg) and deionized water are placed in a beaker at a mass ratio of 1:100 and stirred using a magnetic stirrer for 60 minutes to fully dissolve the NaAlg to form a sodium alginate solution.

[0091] Step 2: Mix neogambogic acid and sodium alginate solution in a volume ratio of 10:100, and stir using a magnetic stirrer for 30 minutes to completely mix them to obtain a mixed solution of sodium alginate and neogambogic acid.

[0092] Step 3: 5 nm Fe2O3 particles were selected as the MNPs of the present invention. The MNPs were added to a mixed solution of sodium alginate and neogambogic acid at a mass ratio of 5:10. The MNPs were evenly dispersed into the mixed solution using an ultrasonic disperser. The solution temperature was maintained below 25°C during the dispersion process. The dispersion was continued for 30 minutes to form a magnetic mixed solution. The magnetic mixed solution was then deaerated using a vacuum degasser and set aside.

[0093] Step 4: Place calcium chloride (CaCl2) and deionized water in a beaker at a mass ratio of 1:100, and stir using a magnetic stirrer for 30 minutes to fully dissolve the CaCl2 to form a calcium chloride solution for later use.

[0094] Step 5: Test bench construction. Figure 1 and Figure 2 As shown, the magnetic mixed solution is contained in the syringe 2, and 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 containing calcium chloride solution. The calcium chloride tube 5 is installed in a two-dimensional magnetic field coil consisting of the first coil 6 (X-axis Helmholtz coil) and the second coil 7 (Y-axis Helmholtz coil). In this embodiment, there is no clear requirement for the coil current, and the magnetic field strength generated by the coil is required to be 10mT.

[0095] Step 6: Microfluidics control and hydrogel microspring formation.

[0096] The microfluidic injection pump 1 is turned on at an injection speed of 3 ml / min, pushing 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 0.4 mm). Sodium alginate reacts with calcium chloride, and Ca 2+ Ion replacement for Na + ions, the outer layer of alginate solution is cross-linked from the outside to the inside into a three-dimensional network of hydrogel, the volume changes, and a magnetic calcium alginate hydrogel microspring is formed.

[0097] Comparative Example 1

[0098] The preparation was based on the paper (Zheng D, Ramos-Sebastian A, Jung WS, 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%, and ultrasonically dispersed for 60 min to obtain a mixed solution.

[0100] 2g of CaCl2 was added to 100ml of deionized water and magnetically stirred for 10 minutes to completely dissolve the CaCl2. The mixed solution was added to a 5ml syringe, and then a capillary was machined into the required bevel angle and connected to the syringe. The tip of the capillary was immersed in the CaCl2 solution and the mixed solution was injected into the CaCl2 solution at a rate of 1.2mL / min to induce a cross-linking reaction and form a spring-shaped hydrogel. Then, a magnetic field strength of 25mT was applied perpendicular to the diameter direction of the spring-shaped hydrogel for 15 minutes to obtain the desired microspring.

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

[0102] The product prepared in Comparative Example 1 lost steps when the rotating magnetic field strength was 4 mT and the rotation frequency was 5, and the microspring could not rotate synchronously with the magnetic field. However, the magnetic calcium alginate hydrogel microsprings prepared in Examples 1 to 6 did not lose steps when the rotating magnetic field strength was 4 mT and the rotation frequency was 14, and continued to rotate synchronously with the magnetic field. Taking the magnetic calcium alginate hydrogel microspring prepared in Example 1 as an example, the linear movement speed of the microspring was approximately 4 mm / s. This proves that the microspring prepared in the present invention has 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, and after the microsprings were initially gelled and formed, the square container containing calcium chloride and microsprings was placed in a one-dimensional Helmholtz coil. The coil power was turned on to generate a magnetic field to sort the MNPs in the microsprings.

[0104] The present invention places a test tube filled with calcium chloride in a two-dimensional Helmholtz coil, starts a microfluidic injection pump and turns on the coil current to generate a rotating magnetic field. During the entire gelation process of microspring molding, the MNPs inside are sorted by the magnetic field.

[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 and has a high degree of automation compared to manually moving the microspring and separately controlling the injection pump and the magnetic field in Comparative Example 1;

[0107] 2. The microspring prepared in Comparative Example 1 has a horizontal axis during the formation process. Under the influence of its own gravity during the formation process, the microspring will bend and sink, affecting the movement performance of the microspring. However, the microspring prepared in the present invention has a vertical axis, which can maintain the uniformity of the spring structure.

[0108] 3. The present invention sorts the MNPs in the microspring throughout the entire process of preparing the magnetic hydrogel microspring, while the method of Comparative Example 1 only sorts the MNPs after the spring is initially formed. The MNP sorting effect of the present invention is better, making the magnetic properties, magnetocaloric properties and motion performance of the microspring better.

[0109] In the present invention, under the action of a static magnetic field, the magnetic nanoparticles (MNPs) rotate so that their magnetic moment is aligned with the direction of the external static magnetic field. Therefore, when a hydrogel containing MNPs is subjected to a static magnetic field, the MNPs in the hydrogel are arranged in a linear manner along the direction of the magnetic field, so that the hydrogel has magnetic anisotropy. According to the calculation formula of the magnetic torque and the magnetothermal conversion mechanism, a hydrogel with magnetic anisotropy will generate a larger magnetic torque and heat generation 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 MNPs therein. At this time, most of the MNPs have been fixed in place by the hydrogel and are difficult to rotate and move, resulting in poor sorting effect. However, the present invention starts sorting at the beginning of the microspring formation and always maintains a fixed diameter direction to rotate synchronously with the microspring. Most of the MNPs can move and rotate freely and are solidified by the hydrogel, so that the MNPs can maintain a good linear sorting state and have 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 may make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0111] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. A method for preparing a magnetic hydrogel microspring, characterized in that: The following steps are involved: Adding neogambogic acid and magnetic nanoparticles to a sodium alginate solution to prepare a magnetic mixed solution; adding calcium chloride to water to prepare a calcium chloride solution; A micro-spring platform is constructed, the micro-spring platform comprising 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) being in communication with the syringe (2), one end of the capillary tube (3) being in communication with the syringe (2), and the other end of the capillary tube (3) being in communication with the calcium chloride tube (5); the first coil (6) and the second coil (7) being arranged vertically to form a two-dimensional magnetic field coil, and the calcium chloride tube (5) being arranged in the two-dimensional magnetic field coil; The magnetic mixed solution is injected into the syringe (2), the calcium chloride solution is injected 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, a magnetic hydrogel microspring is formed.

2. The method for preparing 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 method for preparing 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 method for preparing 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 method for preparing a magnetic hydrogel microspring according to claim 1, characterized in that: The magnetic nanoparticles are Fe2O3 particles.

6. The method for preparing a magnetic hydrogel microspring according to claim 1, characterized in that: The first coil (6) and the second coil (7) are both 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 method for preparing a magnetic hydrogel microspring according to claim 2, characterized in that: The mass concentration of the neogambogic acid in the sodium alginate solution is 1%-20%, and the mass concentration of the magnetic nanoparticles in the mixture of the sodium alginate solution and the neogambogic acid is 10%-20%.

8. The method for preparing 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 microspring prepared according to the preparation method according to any one of claims 1 to 8.

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

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