Six-legged micro-nanorobot with complex environment adaptability

Abstract

The application relates to the field of micro-nano robots, in particular to a six-legged cell puncture micro-nano robot with complex environment adaptability. The structure comprises a core and outer legs, the core is composed of iron oxide, and the outer legs are composed of silicon dioxide. The core material iron oxide of the micro-nano robot has paramagnetism and can respond to an external magnetic field; the six-legged structure generates multiple contact fulcrums in the movement process on the tissue surface with complex topography, facilitates the rolling movement on the tissue surface with complex topography, and can improve the ability of the micro-nano robot to adapt to the complex surface topography of the tissue in the organism. When the micro-nano robot rolls to the top of the cancer cell membrane, the magnetic field generated by the coil is adjusted to be a plane rotating magnetic field, the micro-nano robot rotates at a high frequency around the axis of the vertical horizontal plane; the gradient magnetic field device at the bottom is turned on, the micro-nano robot is subjected to the gradient magnetic force along the direction perpendicular to the cell culture substrate and simultaneously performs the rotating movement and the linear movement, and the effective puncture breakthrough of the cell membrane is realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of micro-nano robots, and more particularly to a six-legged cell puncture micro-nano robot with complex environment adaptability. BACKGROUND

[0002] Traditional treatment methods for cancer include chemotherapy, radiotherapy, hormone therapy, and surgery. These traditional methods have low recognition ability for cancer cells, poor operation efficiency, strong toxic side effects, and can easily harm normal cells in the body, causing damage to the body, and are difficult to achieve precise killing of cancer cells at the single cell level.

[0003] A micro-nano robot is an actuator between microns and nanometers, which can convert external energy into mechanical energy of its own motion. It has the advantages of small size, good controllability, large thrust-to-weight ratio, and strong expandability, and can achieve precise motion control and complex functions in a small environment. It has a very broad application prospect in the field of biomedicine. With the help of the high driving capacity and flexible controllability of the micro-nano robot, and the special design of its configuration, it can be used as a micro-nano scale puncture needle to act on the cell membrane of a single cell, effectively achieving puncture breakthrough of the cell membrane of a single cell without affecting other normal cells, thereby achieving precise killing of cancer cells at the single cell level.

[0004] However, most existing micro-nano robots use chemical fuel or a single external physical field as energy input to drive them, which has the problems of dependence on toxic and harmful fuel, short service life, weak driving capacity, and single control means, making it difficult to meet the puncture requirements of the cell membrane. And the complex and diverse environment in the body, simple configuration of micro-nano robots is difficult to adapt to the complex topography of the tissue surface, and reach the target cell. Therefore, it is urgent to propose a six-legged cell puncture micro-nano robot with complex environment adaptability and its preparation method, which can adapt to the complex surface topography of the tissue in the body and overcome the limitations of existing micro-nano robots in cell puncture, and ultimately achieve precise killing of cancer cells at the single cell level. SUMMARY

[0005] To overcome the shortcomings of the prior art, the present application provides a six-legged cell puncture micro-nano robot with complex environment adaptability and its preparation method, which has the advantages of being able to adapt to the complex surface topography of the tissue in the body and overcoming the limitations of existing micro-nano robots in cell puncture.

[0006] The technical scheme adopted by the present application to solve its technical problems is:

[0007] The present application aims to provide a six-legged cell puncture micro-nano robot with complex environment adaptability, which comprises a core and an outer leg, the core is composed of iron oxide, and the outer leg is composed of silicon dioxide.

[0008] A preparation method of a hexapod cell puncture micro-nano robot with complex environment adaptability, comprising the following steps:

[0009] Step one: using chemical method to prepare cubic iron oxide particles;

[0010] Step two: using sol-gel process and chemical precipitation process to grow rod-shaped silicon dioxide around the cubic iron oxide particles;

[0011] Step three: centrifugation and washing to obtain hexapod micro-nano robot.

[0012] A preparation method of a hexapod cell puncture micro-nano robot with complex environment adaptability, the process of step one is:

[0013] (1) slowly add sodium hydroxide solution to iron chloride solution, and stir with a mechanical stirrer during the process, which lasts for 10-15 minutes;

[0014] (2) then continue to stir with a mechanical stirrer for 5-10 minutes, transfer the obtained solution to a glass bottle, and heat in a muffle furnace at 95-100℃ for 8 days;

[0015] (3) finally, add the obtained reaction product into anhydrous ethanol and deionized water for centrifugation and washing 3 times, and dry the obtained precipitate in a drying oven at 60-80℃ for 12 hours to obtain the cubic core of hexapod micro-nano robot, i.e. cubic iron oxide particles.

[0016] A preparation method of a hexapod cell puncture micro-nano robot with complex environment adaptability, the process of step two is:

[0017] (1) disperse the obtained iron oxide cubic core in deionized water to form an iron oxide colloid with a concentration of 5wt%;

[0018] (2) mix polyvinylpyrrolidone and n-pentanol in an Erlenmeyer flask, and stir in a constant temperature heating magnetic stirrer at 80℃ for 1-2 hours, then sequentially add iron oxide colloid, ethanol, deionized water, and sodium citrate solution, and continue to stir in the constant temperature heating magnetic stirrer at 80℃ for 1 minute;

[0019] (3) then add ammonia water and shake for 3 minutes, and then add tetraethyl silicate and shake for 5 minutes, and react at room temperature for 12 hours to grow rod-shaped silicon dioxide around the cubic iron oxide particles.

[0020] A preparation method of a hexapod cell puncture micro-nano robot with complex environment adaptability, the process of step three is:

[0021] The obtained reaction product is removed from the supernatant, anhydrous ethanol and deionized water are added in sequence, centrifuged and washed three times, and a solution containing the hexapod micro-nano robot is obtained.

[0022] A double-mode magnetic drive control device for a hexapod cell puncture micro-nano robot with complex environment adaptability, the double-mode magnetic drive control device comprising a microscope, a magnetic field generating device and a gradient magnetic field device;

[0023] The magnetic field generating device adopts three groups of Helmholtz coils, a signal generator is used as an alternating current signal source to generate a sine wave signal, the electrical signal is amplified by a power amplifier, and is input into the Helmholtz coils to generate a uniform magnetic field in any plane in a three-dimensional space to drive the hexapod micro-nano robot to rotate along any axis.

[0024] The gradient magnetic field device has an electromagnet as the main part, a signal generator is used as a direct current signal source to generate a stable direct current signal, the electrical signal is amplified by a power amplifier, and is input into the electromagnet to provide a stable gradient magnetic field perpendicular to the cell culture substrate in the experimental area to enhance the vertical movement ability of the hexapod micro-nano robot; the micro-nano robot experimental area is located at the center of the Helmholtz coils, which provides support.

[0025] The core material of the micro-nano robot, iron oxide, has paramagnetism and can respond to an external magnetic field; when a uniform rotating magnetic field is applied, the micro-nano robot rolls around the axis in response to the magnetic field. The micro-nano robot can quickly respond to the external magnetic field and generate magnetization, and exhibits movement behavior under the action of the magnetic field.

[0026] The hexapod cell puncture micro-nano robot can rotate along any axis, change the direction of the uniform rotating magnetic field generated by the Helmholtz coils, and control the speed and direction of the micro-nano robot. The hexapod cell puncture micro-nano robot has controllable movement and can achieve precise control of speed and direction.

[0027] The micro-nano robot has a hexapod structure, which produces multiple contact points during movement on the surface of a tissue with complex topography, facilitating rolling movement on the surface of a tissue with complex topography, and improving the ability of the micro-nano robot to adapt to the complex surface topography of tissues in the body.

[0028] When the micro-nano robot rolls to the top of the cancer cell membrane, the magnetic field generated by the coil is adjusted to a planar rotating magnetic field, the micro-nano robot is subjected to a magnetic torque in the horizontal plane and rotates at a high frequency around the vertical horizontal axis; at the same time, the gradient magnetic field device at the bottom is turned on, the micro-nano robot moves downward under the action of the gradient magnetic force perpendicular to the cell culture substrate, while rotating and moving linearly, effectively puncturing and breaking through the cell membrane.

[0029] The beneficial effects of the hexapod cell puncture micro / nano robot with complex environmental adaptability of the present invention are as follows:

[0030] The fabricated hexapod micro / nano robot can respond quickly to external magnetic fields and become magnetized, exhibiting motion behavior under the influence of magnetic fields;

[0031] The fabricated hexapod micro-nano robot can rotate along any axis. By controlling the strength and direction of the uniform rotating magnetic field generated by the Helmholtz coil, precise control of the movement speed and direction of the micro-nano robot can be achieved.

[0032] The fabricated hexapod micro-nano robot can significantly increase the contact fulcrum with tissue surfaces with complex morphology in vivo and perform tumbling motions above them, greatly improving the adaptability of the micro-nano robot to the complex surface morphology of tissues in vivo.

[0033] During cell puncture, the micro-nano robot can simultaneously perform rotational and linear motion under the coupling of a rotating magnetic field and a gradient magnetic field, thus breaking through the cell membrane barrier.

[0034] Using hexapod micro-nano robots for cell puncture can replace existing artificial cell puncture methods, achieving precise killing of cancer cells and saving traditional medical resources. Attached Figure Description

[0035] The present invention will now be described in further detail with reference to the accompanying drawings and specific implementation methods.

[0036] Appendix Figure 1 A schematic diagram illustrating the synthesis process of a hexapod cell puncture micro / nano robot with complex environmental adaptability;

[0037] Appendix Figure 2 Scanning electron microscope image and energy dispersive spectroscopy (EDS) image of a hexapod cell puncture micro / nano robot with complex environmental adaptability;

[0038] Appendix Figure 3 A diagram showing the components of a dual-mode magnetic drive control device for a hexapod cell puncture micro / nano robot with complex environmental adaptability;

[0039] Appendix Figure 4 This is an experimental diagram of the motion control of a hexapod cell puncture micro / nano robot with complex environmental adaptability under a uniform rotating magnetic field.

[0040] Appendix Figure 5 This is a schematic diagram of the magnetically driven motion and membrane rupture process of a hexapod cell puncture micro / nano robot with complex environmental adaptability;

[0041] Appendix Figure 6 This image shows the characterization of a hexapod cell puncture micro / nanorobot with complex environmental adaptability during a cell puncture experiment under a dual-mode magnetic field.

[0042] In the figure: microscope 1; Helmholtz coil 2; power amplifier 3; AC signal source 4; DC signal source 5; gradient magnetic field device 6; micro-nano robot experimental area 7. DETAILED DESCRIPTION

[0043] A hexapod cell puncture micro-nano robot with complex environmental adaptability comprises a core and outer legs, wherein the core is composed of iron oxide, and the outer legs are composed of silicon dioxide.

[0044] A preparation method of a hexapod cell puncture micro-nano robot with complex environmental adaptability comprises the following steps:

[0045] Step one: preparing cubic iron oxide particles by a chemical method;

[0046] Step two: growing rod-shaped silicon dioxide around the cubic iron oxide particles by a sol-gel process and a chemical precipitation process;

[0047] Step three: centrifuging and washing to obtain the hexapod micro-nano robot.

[0048] A preparation method of a hexapod cell puncture micro-nano robot with complex environmental adaptability comprises the following steps:

[0049] The process of step one is as follows:

[0050] (1) slowly drop sodium hydroxide solution (90 mL, 5 mol / L) into iron chloride solution (100 mL, 2 mol / L), and stir with a mechanical stirrer during the dropping process, which lasts for 10-15 minutes, preferably 12 minutes;

[0051] (2) then continue to stir with the mechanical stirrer for 5-10 minutes, preferably 8 minutes, transfer the obtained solution to a glass bottle (250 mL), and place it in a muffle furnace at 95-100℃, preferably 100℃, and heat for 8 days;

[0052] (3) finally, add the obtained reaction product into anhydrous ethanol and deionized water, respectively, centrifuge and wash 3 times, and place the obtained precipitate in a drying oven at 60-80℃, preferably 80℃, and dry for 12 hours, to obtain the cubic core of the hexapod micro-nano robot.

[0053] The process of step two is as follows:

[0054] (1) disperse the obtained iron oxide cubic core into deionized water to form an iron oxide colloid with a concentration of 5wt%;

[0055] (2) polyvinylpyrrolidone (1 g) is mixed with n-pentanol (10 mL) in a conical flask (50 mL) and stirred in a constant temperature heating magnetic stirrer at 80 DEG C for 1-2 hours, preferably 2 hours, then iron oxide colloid (100 μL, 5 wt%) is added, followed by ethanol (1 mL), deionized water (200 μL), sodium citrate solution (100 μL, 0.2 mol / L), and constant temperature magnetic stirring is continued at 80 DEG C for 1 minute;

[0056] (3) then ammonia (200 μL, 28 wt%) is added, stirred for 3 minutes, tetraethyl silicate (150 μL) is added, stirred for 5 minutes, and reaction is carried out at room temperature for 12 hours.

[0057] The process of step three is as follows:

[0058] The obtained reaction product is removed from the supernatant, anhydrous ethanol and deionized water are added in sequence, centrifuged and washed 3 times, and a solution containing the hexapod micro-nano robot is obtained.

[0059] The synthesis process of the above hexapod micro-nano robot is shown in Figure 1 .

[0060] The prepared hexapod micro-nano robot is characterized by a scanning electron microscope and an energy spectrometer, and the characterization results are shown in Figure 2 . Analysis of the characterization results shows that the core of the micro-nano robot is composed of iron oxide material, and the outer leg is composed of silicon dioxide material.

[0061] A dual-mode magnetic drive control device for a hexapod cell puncture micro-nano robot with complex environment adaptability, the dual-mode magnetic drive control device comprising a microscope 1, a magnetic field generating device and a gradient magnetic field device 6;

[0062] The magnetic field generating device adopts three groups of Helmholtz coils 2, a signal generator is used as an alternating current signal source 4 to generate a sine wave signal, the sine wave signal is 4V, the electrical signal is amplified 2-5 times by a power amplifier 3, and then input into the Helmholtz coil 2, so as to generate a three-direction magnetic field in the experimental area, control the size and direction of each direction magnetic field, and form a uniform rotating magnetic field in any plane to drive the hexapod micro-nano robot to rotate along any axis and perform rolling motion;

[0063] The gradient magnetic field device 6 is mainly composed of an electromagnet, and a signal generator is used as a direct current signal source 5 to generate a stable direct current signal, which is amplified by a power amplifier 3 and then input into the electromagnet, so that the electromagnet provides a stable gradient magnetic field perpendicular to the cell culture substrate in the experimental area, so that the micro-nano robot is subjected to a vertical magnetic field force, and the vertical movement ability of the six-legged micro-nano robot in the membrane breaking process is enhanced; the micro-nano robot experimental area 7 is located at the center of the Helmholtz coil, and is supported by the Helmholtz coil. It is used for placing cell culture dishes, twenty-four-hole cell culture plates and other experimental object culture containers. Microscopes are used for observation.

[0064] The core of the six-legged micro-nano robot suitable for complex environment is composed of paramagnetic iron oxide material, which is magnetized under the action of an external magnetic field, and an induced magnetic dipole moment is formed inside, the magnetic dipole moment interacts with the external magnetic field, and a magnetic torque is generated, which drives the micro-nano robot to rotate until the direction of the induced magnetic dipole moment inside is parallel to the direction of the external magnetic field.

[0065] Further, by controlling the absolute size of the electric signal amplitude in each coil of the Helmholtz coil 2, the magnetic field strength of the uniform rotating magnetic field is adjusted, and then the movement speed of the micro-nano robot is controlled; by controlling the relative size of the phase difference and amplitude of the electric signal in each coil of the Helmholtz coil 2, a uniform rotating magnetic field can be formed in any plane, and then the movement direction of the micro-nano robot is controlled.

[0066] The controllability of the movement of the six-legged micro-nano robot under the magnetic field is as shown in Figure 4 When the Helmholtz coil 2 is connected to the electric signal, the micro-nano robot quickly changes from a static state to a moving state. Since the core of the micro-nano robot has paramagnetism, the strength of the current in the Helmholtz coil 2 can be changed to accurately control the movement speed of the six-legged micro-nano robot; the direction of the combined magnetic field generated by the Helmholtz coil 2 is changed to accurately control the movement direction of the six-legged micro-nano robot.

[0067] Due to the special six-legged structure of the six-legged micro-nano robot, the contact points can be significantly increased when the robot moves on the surface of the tissue with complex morphology in the body, and the ability of the micro-nano robot to adapt to the complex surface morphology of the tissue in the body can be greatly improved. When the six-legged micro-nano robot is controlled by the uniform rotating magnetic field to cross the surface with complex morphology and approach the target cell, it continues to roll on the cell membrane and then moves to the top of the target cell. At this time, the Helmholtz coil 2 generates a uniform rotating magnetic field in the horizontal plane, and the micro-nano robot can self-rotate at a high frequency above the cell, and at the same time, the gradient magnetic field device 6 at the bottom is turned on, so that the micro-nano robot moves downward under the action of the vertical magnetic force, and the ability to pierce the cell membrane is further improved. The schematic diagram of the above-mentioned magnetic driving movement and membrane breaking process of the six-legged micro-nano robot is as shown in Figure 5The six-legged micro-nanorobot can perform rotational motion and linear motion simultaneously to break through the cell membrane barrier after the application of an external rotating magnetic field and a gradient magnetic field.

[0068] The effect of the six-legged micro-nanorobot penetrating the cell membrane is shown in FIG. 6. Figure 6 As shown in FIG. 6, the cells are dyed green using calcein before penetration, proving that they have cell activity. Then, the six-legged micro-nanorobot is added, the magnetic field strength and direction generated by the Helmholtz coil 2 are changed, the motion speed and direction of the six-legged micro-nanorobot are controlled, the six-legged micro-nanorobot is made to approach the target cell and roll to the top of the cell. The magnetic field generated by the Helmholtz coil 2 is immediately changed to a uniform rotating magnetic field in the horizontal plane, and it is observed that the six-legged micro-nanorobot rotates at a high frequency on the surface of the cell. At the same time, the gradient magnetic field device 6 below the experimental area is turned on, and the six-legged micro-nanorobot rotates while being subjected to a downward magnetic force and thus moves downward. After a period of time, the cells are dyed red using propidium iodide, proving that the cells are dead, and the micro-nanorobot successfully realizes penetration and breakthrough of the cell.

Claims

1. A hexapod cell-penetrating micro-nanorobot system with complex environment adaptability, comprising a hexapod cell-penetrating micro-nanorobot and a dual-mode magnetic drive control device, characterized in that: The hexapod cell-penetrating micro-nanorobot comprises a core and outer legs, the core is made of iron oxide, and the outer legs are made of silicon dioxide; The preparation method of the hexapod cell-penetrating micro-nanorobot comprises the following steps: Step one: cubic iron oxide particles are prepared by a chemical method; Step two: rod-shaped silicon dioxide is grown around the cubic iron oxide particles by a sol-gel process and a chemical precipitation process; Step three: the hexapod micro-nanorobot is obtained by centrifugation and washing; The process of step one is as follows: (1) sodium hydroxide solution is slowly added to iron chloride solution, and mechanical stirring is performed during the adding process, and the stirring process lasts for 10-15 minutes; (2) then the stirring is continued for 5-10 minutes by using a mechanical stirrer, and the obtained solution is transferred to a glass bottle and heated in a muffle furnace at 95-100 DEG C for 8 days; (3) finally, the obtained reaction product is added into anhydrous ethanol and deionized water for centrifugation and washing for 3 times, and the obtained precipitate is dried in a drying oven at 60-80 DEG C for 12 hours to obtain the cubic core of the hexapod micro-nanorobot, i.e. the cubic iron oxide particles; The process of step two is as follows: (1) the obtained iron oxide cubic core is dispersed in deionized water to form an iron oxide colloid with a concentration of 5 wt%; (2) polyvinylpyrrolidone and n-pentanol are mixed and placed in a conical flask, and stirred in a constant-temperature heating magnetic stirrer at 80 DEG C for 1-2 hours, and then the iron oxide colloid, ethanol, deionized water and sodium citrate solution are sequentially added, and the magnetic stirring is continued at 80 DEG C for 1 minute; (3) then ammonia water is added and shaken for 3 minutes, and then tetraethyl silicate is added and shaken for 5 minutes, and the rod-shaped silicon dioxide is grown around the cubic iron oxide particles at room temperature for 12 hours.

2. The hexapod cell-puncturing micro-nanorobot system with complex environment adaptability according to claim 1, characterized in that: The process of step three is as follows: The obtained reaction product is removed from the supernatant, and then anhydrous ethanol and deionized water are added for centrifugation and washing for 3 times to obtain a solution containing the hexapod micro-nanorobot.

3. The hexapod cell-puncturing micro-nanorobot system with complex environment adaptability according to claim 1, characterized in that: The dual-mode magnetic drive control device comprises a microscope (1), a magnetic field generating device and a gradient magnetic field device (6); The magnetic field generating device adopts three groups of Helmholtz coils (2), the signal generator is used as an alternating current signal source (4) to generate a sine wave signal, the power amplifier (3) is used to amplify the electrical signal, and the signal is input into the Helmholtz coil to generate a uniform magnetic field in any plane in the three-dimensional space to drive the hexapod micro-nanorobot to rotate along any axis; The gradient magnetic field device (6) mainly comprises an electromagnet, the signal generator is used as a direct current signal source (5) to generate a stable direct current signal, the power amplifier (3) is used to amplify the electrical signal, and then the signal is input into the electromagnet, and the electromagnet provides a stable gradient magnetic field perpendicular to the cell culture substrate in the experimental area to enhance the vertical movement ability of the hexapod micro-nanorobot; the micro-nanorobot experimental area (7) is located at the center of the Helmholtz coil, and the Helmholtz coil provides support.

4. The hexapod cell-puncturing micro-nanorobot system with complex environment adaptability according to claim 3, characterized in that: The core material of the micro-nanorobot, iron oxide, has paramagnetism and can respond to an external magnetic field; when a uniform rotating magnetic field is applied, the micro-nanorobot rolls around the axis in response to the magnetic field.

5. The hexapod cell-puncturing micro-nanorobot system with complex environment adaptability according to claim 3, characterized in that: The six-legged cell puncture micro-nano robot can rotate along any axis, change the direction of the uniform rotating magnetic field generated by the Helmholtz coil, and accurately control the movement speed and direction of the micro-nano robot.

6. The hexapod cell-puncturing micro-nanorobot system with complex environment adaptability according to claim 1, characterized in that: The micro-nano robot has a six-legged structure, which generates multiple contact support points during movement on a tissue surface with complex topography, facilitates rolling movement on the complex topography of the tissue surface, and greatly improves the ability of the micro-nano robot to adapt to the complex surface topography of the tissue in the organism.

7. The hexapod cell-puncturing micro-nanorobot system with complex environment adaptability according to claim 3, characterized in that: When the micro-nano robot rolls to the top of the cancer cell membrane, the magnetic field generated by the coil is adjusted to be a planar rotating magnetic field, the micro-nano robot is subjected to a magnetic torque in the horizontal plane, and rotates at a high frequency around the vertical horizontal axis; at the same time, the gradient magnetic field device (6) at the bottom is turned on, the micro-nano robot is subjected to a gradient magnetic force along the direction perpendicular to the cell culture substrate and moves downward, while rotating and moving linearly, thereby effectively puncturing and breaking through the cell membrane.

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