Hexapod cell puncture micro-nano robot with complex environment adaptability

Abstract

The invention relates to the field of micro-nano robots, in particular to a hexapod cell puncture micro-nano robot with complex environment adaptability. The structure comprises a core and an outer foot, the core is made of iron oxide, and the outer foot is made 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-foot structure generates multiple contact fulcrums in the movement process of the tissue surface with the complex morphology, rolling movement on the tissue surface with the complex morphology is facilitated, and the capacity of the micro-nano robot for adapting to the complex surface morphology of the tissue in a living body can be improved. When the micro-nano robot rolls over the cancer cell membrane along the cancer cell membrane, the magnetic field generated by the coil is adjusted to be a plane rotating magnetic field, and the micro-nano robot rotates at high frequency in the axial direction perpendicular to the horizontal plane; the gradient magnetic field device at the bottom is started, the micro-nano robot rotates and linearly moves under the action of gradient magnetic force in the direction perpendicular to the cell culture substrate, and effective puncture breakthrough on cell membranes is achieved.

Description

Technical Field

[0001] The present invention relates to the field of micro-nanorobots, and more specifically, to a six-legged cell-puncturing micro-nanorobot with complex environmental adaptability. Background Art

[0002] Traditional treatment methods for cancer include chemotherapy, radiotherapy, hormone therapy, surgical operation, etc. These traditional methods have low recognition ability for cancer cells, poor operation efficiency, strong toxic and side effects, are prone to damage good cells in the body, cause damage to the body, and it is difficult to achieve precise killing of cancer cells at the single-cell level.

[0003] A micro-nanorobot is an actuator between the micron and nanometer scales, which can convert external energy into mechanical energy of its own movement. It has advantages such as small size, good controllability, large thrust-to-weight ratio, and strong expandability. It can achieve precise motion control and complex functions in a microenvironment and has extremely broad application prospects in the field of biomedicine. By virtue of the efficient driving ability and flexible controllability of the micro-nanorobot and through special design of its configuration, it can be used as a puncture needle at the micro-nano scale 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 precisely killing cancer cells at the single-cell level.

[0004] However, most of the existing micro-nanorobots use chemical fuels or a single external physical field as energy input for driving, and there are problems such as dependence on toxic and harmful fuels, short lifespan, weak driving ability, and single control means, which are difficult to meet the puncture requirements for the cell membrane; moreover, the biological internal environment is complex and diverse, and micro-nanorobots with simple configurations are difficult to adapt to the tissue surface with complex morphological features and reach the target cells. Therefore, there is an urgent need to propose a six-legged cell-puncturing micro-nanorobot with complex environmental adaptability and its preparation method, which can not only adapt to the complex surface morphology of tissues in the body but also overcome the limitations of existing micro-nanorobots in cell puncture, and finally achieve precise killing of cancer cells at the single-cell level. Summary of the Invention

[0005] To overcome the deficiencies of the prior art, the present invention provides a six-legged cell-puncturing micro-nanorobot with complex environmental adaptability and its preparation method, and its beneficial effect is that it can adapt to the complex surface morphology of tissues in the body and overcome the limitations of existing micro-nanorobots in cell puncture.

[0006] The technical solution adopted by the present invention to solve its technical problems is:

[0007] The object of the present invention is to provide a six-legged cell-puncturing micro-nanorobot with complex environmental adaptability, including a core and outer legs. The core is composed of iron oxide, and the outer legs are composed of silicon dioxide.

[0008] A preparation method of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability, comprising the following steps:

[0009] Step 1: Prepare cubic iron oxide particles by chemical methods;

[0010] Step 2: Grow rod-shaped silica around the cubic iron oxide particles by sol-gel process and chemical precipitation process;

[0011] Step 3: Centrifuge and wash to obtain a six-legged micro-nano robot.

[0012] A preparation method of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability, the process of the first step is as follows:

[0013] (1) Slowly drop the sodium hydroxide solution into the ferric chloride solution, and stir with a mechanical stirrer during the dropping process, and this stirring process lasts for 10-15 minutes;

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

[0015] (3) Finally, add anhydrous ethanol and deionized water to the obtained reactants in sequence for centrifugation and washing 3 times, place the obtained precipitate in a drying oven and dry it at 60-80 °C for 12 hours to obtain the cubic core of the six-legged micro-nano robot, that is, cubic iron oxide particles.

[0016] A preparation method of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability, the process of the second step is as follows:

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

[0018] (2) Mix polyvinylpyrrolidone and n-pentanol and place them in a conical flask, and stir them in a thermostatic heating magnetic stirrer at 80 °C for 1-2 hours. Subsequently, add the iron oxide colloid, ethanol, deionized water, and sodium citrate solution in sequence, and continue magnetic stirring at 80 °C for 1 minute;

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

[0020] A preparation method of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability, the process of the third step is as follows:

[0021] Take the obtained reactants, remove the supernatant, and successively add absolute ethanol and deionized water for centrifugation and washing three times to obtain a solution containing hexapod micro-nanorobots.

[0022] A dual-mode magnetic drive control device for a hexapod cell-puncturing micro-nanorobot with complex environment adaptability, the dual-mode magnetic drive control device includes a microscope, a magnetic field generating device, and a gradient magnetic field device;

[0023] The magnetic field generating device uses three sets of Helmholtz coils. The signal generator is used as an AC signal source to generate a sine wave signal. The electrical signal is amplified by a power amplifier and input into the Helmholtz coils to generate a uniform magnetic field in any plane in three-dimensional space, driving the hexapod micro-nanorobot to rotate along any axis;

[0024] The main part of the gradient magnetic field device is an electromagnet. The signal generator is used as a DC signal source to generate a stable DC signal. The electrical signal is amplified by a power amplifier and then input into the electromagnet. The electromagnet provides a stable gradient magnetic field perpendicular to the cell culture medium bottom in the experimental area, enhancing the vertical movement ability of the hexapod micro-nanorobot; The experimental area of the micro-nanorobot is located at the exact center of the Helmholtz coils and is supported by the Helmholtz coils.

[0025] 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 due to magnetic response. The micro-nanorobot can quickly respond to an external magnetic field and become magnetized, showing a motion behavior under the action of the magnetic field.

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

[0027] The micro-nanorobot has a hexapod structure. During the movement of the hexapod structure on the surface of tissues with complex morphologies, multiple contact fulcrums are generated, facilitating rolling movement on the surface of tissues with complex morphologies and improving the ability of the micro-nanorobot to adapt to the complex surface morphologies of tissues in the body.

[0028] When the micro-nanorobot rolls to directly above the cancer cell membrane, adjust the magnetic field generated by the coil to a planar rotating magnetic field. The micro-nanorobot is subjected to a magnetic torque in the horizontal plane and rotates at a high frequency around the axis perpendicular to the horizontal plane; at the same time, turn on the gradient magnetic field device at the bottom. The micro-nanorobot is subjected to a gradient magnetic force in the direction perpendicular to the cell culture medium bottom and moves downward, while performing rotational motion and linear motion to achieve effective puncture and breakthrough of the cell membrane.

[0029] The beneficial effects of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability of the present invention are as follows:

[0030] The prepared six-legged micro-nano robot can quickly respond to an external magnetic field and become magnetized, showing a motion behavior under the action of the magnetic field;

[0031] The prepared six-legged micro-nano robot can rotate along any axis. By controlling the intensity and direction of the uniform rotating magnetic field generated by the Helmholtz coil, precise control of the motion speed and direction of the micro-nano robot can be achieved;

[0032] The prepared six-legged micro-nano robot can significantly increase the contact fulcrums with the surface of tissues with complex morphologies in the body and perform tumbling motions above them, greatly improving the adaptability of the micro-nano robot to the complex surface morphologies of tissues in the body;

[0033] During the process of puncturing cells, the micro-nano robot can simultaneously perform rotational motion and linear motion under the coupling of a rotating magnetic field and a gradient magnetic field, achieving a breakthrough of the cell membrane barrier;

[0034] Using the six-legged micro-nano robot for cell puncture can replace the existing manual cell puncture means, achieve precise killing of cancer cells, and save traditional medical resources. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0036] FIG Figure 1 is a schematic diagram of the synthesis process of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability;

[0037] FIG Figure 2 is a scanning electron microscope image and an energy spectrum diagram of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability;

[0038] FIG Figure 3 is a composition diagram of a dual-mode magnetic drive control device for a six-legged cell-puncturing micro-nano robot with complex environmental adaptability;

[0039] FIG Figure 4 is an experimental diagram of the motion control of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability under a uniform rotating magnetic field;

[0040] FIG Figure 5 is a schematic diagram of the magnetic drive motion and membrane rupture process of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability;

[0041] FIG Figure 6 is an experimental characterization diagram of cell puncture of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability 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. Specific implementation method

[0043] A six-legged cell-puncturing micro-nano robot with complex environmental adaptability, including a core and outer legs. The core is composed of iron oxide, and the outer legs are composed of silica.

[0044] A preparation method of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability includes the following steps:

[0045] Step 1: Prepare cubic iron oxide particles by chemical methods;

[0046] Step 2: Grow rod-shaped silica around the cubic iron oxide particles by sol-gel process and chemical precipitation process;

[0047] Step 3: Centrifuge and wash to obtain a six-legged micro-nano robot.

[0048] A preparation method of a six-legged cell-puncturing micro-nano robot with complex environmental adaptability:

[0049] The process of Step 1 is as follows:

[0050] (1) Slowly add sodium hydroxide solution (90 mL, 5 mol / L) to ferric chloride solution (100 mL, 2 mol / L), and stir with a mechanical stirrer during the addition process. This stirring process lasts for 10 - 15 minutes, preferably 12 minutes;

[0051] (2) Then continue to stir with a mechanical stirrer for 5 - 10 minutes, preferably 8 minutes. Transfer the stirred solution to a glass bottle (250 mL), place it in a muffle furnace at 95 - 100 °C, preferably 100 °C, and heat for 8 days;

[0052] (3) Finally, add anhydrous ethanol and deionized water to the obtained reactants in sequence for centrifugation and washing 3 times. Place the obtained precipitate in a drying oven at 60 - 80 °C, preferably 80 °C, and dry for 12 hours to obtain the cubic core of the six-legged micro-nano robot.

[0053] The process of Step 2 is as follows:

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

[0055] (2) Mix polyvinylpyrrolidone (1 g) with n-pentanol (10 mL) in a conical flask (50 mL), and stir in a constant-temperature heating magnetic stirrer at 80 °C for 1 - 2 hours, preferably 2 hours. Subsequently, add iron oxide colloid (100 μL, 5 wt%), ethanol (1 mL), deionized water (200 μL), and sodium citrate solution (100 μL, 0.2 mol / L) in sequence, and continue magnetic stirring at 80 °C for 1 minute;

[0056] (3) Then add ammonia water (200 μL, 28 wt%), shake well for 3 minutes, and then add tetraethyl orthosilicate (150 μL), shake well for 5 minutes, and react at room temperature for 12 hours.

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

[0058] Take the obtained reactant to remove the supernatant, and successively add absolute ethanol and deionized water for centrifugation and washing 3 times to obtain a solution containing hexapod micro-nanorobots.

[0059] The schematic diagram of the synthesis process of the above hexapod micro-nanorobot is as Figure 1 shown.

[0060] Characterize the prepared hexapod micro-nanorobot using a scanning electron microscope and an energy spectrometer, and the characterization results are as Figure 2 shown. Analyzing the characterization results, it can be seen that the core of the micro-nanorobot is composed of iron oxide material, and the outer feet are composed of silica material.

[0061] A dual-mode magnetic drive control device for a hexapod cell-puncturing micro-nanorobot with complex environmental adaptability, the dual-mode magnetic drive control device includes a microscope 1, a magnetic field generating device, and a gradient magnetic field device 6;

[0062] The magnetic field generating device uses three groups of Helmholtz coils 2. Use a signal generator as an AC signal source 4 to generate a sine wave signal. The sine wave signal is 4 V. The electrical signal is amplified 2 - 5 times by a power amplifier 3 and then input into the Helmholtz coils 2, which can generate a three-directional magnetic field in the experimental area. Controlling the magnitude and direction of the magnetic field in each direction can form a uniform rotating magnetic field in any plane, driving the hexapod micro-nanorobot to rotate along any axis and perform tumbling motion;

[0063] The main component of the gradient magnetic field device 6 is an electromagnet. A signal generator 5 serves as a DC signal source, generating a stable DC signal. This signal is amplified by a power amplifier 3 and then input into the electromagnet. The electromagnet provides a stable gradient magnetic field perpendicular to the cell culture substrate within the experimental area. This forces the micro-nano robot in a vertical direction, enhancing the hexapod's vertical motion during the membrane disruption process. The micro-nano robot experimental area 7 is located at the exact center of the Helmholtz coil and is supported by the coil. It is used to place experimental culture vessels such as cell culture dishes and 24-well cell culture plates. Observation is performed using a microscope.

[0064] The core of the hexapod micro-nano robot proposed in the present invention, which is adaptable to complex environments, is made of paramagnetic iron oxide material. It is magnetized under the action of an external magnetic field, forming an induced magnetic dipole moment inside. The magnetic dipole moment interacts with the external magnetic field and generates a magnetic torque, driving the micro-nano robot to rotate until the direction of its internal induced magnetic dipole moment is parallel to the direction of the external magnetic field.

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

[0066] The motion controllability of hexapod micro-nano robot under magnetic field Figure 4 As shown in the figure, when the Helmholtz coil 2 is connected to an electrical signal, the micro-nano robot rapidly transitions from a static state to a dynamic state. Because the micro-nano robot core is paramagnetic, the hexapod's speed can be precisely controlled by varying the current intensity within the Helmholtz coil 2. The hexapod's direction of motion can also be precisely controlled by varying the direction of the synthetic magnetic field generated by the Helmholtz coil 2.

[0067] Due to the special six-legged structure of the hexapod micro-nano robot, it can significantly increase the contact fulcrums when it moves on the surface of tissue with complex morphology in the body, which can greatly improve the ability of the micro-nano robot to adapt to the complex surface morphology of tissue in the body. When the hexapod micro-nano robot is controlled by a uniform rotating magnetic field to climb over a surface with complex morphology and approach the target cell, it continues to roll on the cell membrane and then moves to just above the target cell. At this time, the Helmholtz coil 2 is controlled to generate a uniform rotating magnetic field in the horizontal plane, and the micro-nano robot can rotate at a high frequency above the cell. At the same time, the gradient magnetic field device 6 at the bottom is turned on, and the micro-nano robot moves downward under the action of the vertical magnetic force, further improving its ability to puncture the cell membrane. The schematic diagram of the magnetic drive movement and membrane rupture process of the above-mentioned hexapod micro-nano robot is shown in the figure below. Figure 5As shown in the figure. After applying an external rotating magnetic field and a gradient magnetic field, the hexapod micro-nanorobot can perform rotational motion and linear motion simultaneously, achieving the breakthrough of the cell membrane barrier.

[0068] The effect of the hexapod micro-nanorobot puncturing the cell membrane is as Figure 6 shown in the figure. Using calcein staining, the cells were green before puncture, indicating cell viability. Subsequently, the hexapod micro-nanorobot was added. The magnetic field intensity and direction generated by the Helmholtz coil 2 were changed to control the movement speed and direction of the hexapod micro-nanorobot, making it approach the target cell and roll to directly above the cell. Immediately afterwards, the magnetic field generated by the Helmholtz coil 2 was changed to a uniform rotating magnetic field in the horizontal plane. It was observed that the hexapod micro-nanorobot rotated at a high frequency on the upper surface of the cell. At the same time, the gradient magnetic field device 6 directly below the experimental area was turned on. The hexapod micro-nanorobot moved downward while rotating under the action of the downward magnetic force. After a period of time, using propidium iodide staining, the cells were red, indicating cell death, and the micro-nanorobot successfully achieved the puncture breakthrough of the cells.

Claims

1. A six-legged cell puncturing micro-nano robot with complex environmental adaptability, comprising a core and outer legs, characterized in that: The core is composed of iron oxide, and the outer feet are composed of silicon dioxide.

2. A method for preparing a six-legged cell puncturing micro-nano robot with complex environmental adaptability according to claim 1, comprising the following steps: Step 1: Prepare cubic iron oxide particles by a chemical method; Step 2: Grow rod-shaped silicon dioxide around the cubic iron oxide particles by a sol-gel process and a chemical precipitation process; Step 3: Centrifuge and wash to obtain a six-legged micro-nano robot.

3. A six-legged cell puncturing micro-nano robot with complex environmental adaptability according to claim 2, characterized in that: The process of Step 1 is as follows: (1) Slowly drip a sodium hydroxide solution into a ferric chloride solution, and stir with a mechanical stirrer during the dripping process. This stirring process lasts for 10-15 minutes; (2) Then continue to stir with a mechanical stirrer for 5-10 minutes, transfer the stirred solution to a glass bottle, and place it in a muffle furnace for heating at 95-100 °C for 8 days; (3) Finally, add anhydrous ethanol and deionized water to the obtained reactants in sequence for centrifugation and washing 3 times, and place the obtained precipitate in a drying oven for drying at 60-80 °C for 12 hours to obtain the cubic core of the six-legged micro-nano robot, that is, cubic iron oxide particles.

4. The six-legged cell puncturing micro-nano robot with complex environment adaptability according to claim 3, wherein: The process of Step 2 is as follows: (1) Disperse the obtained iron oxide cubic core in deionized water to form an iron oxide colloid with a concentration of 5 wt%; (2) Mix polyvinylpyrrolidone and n-pentanol and place them in a conical flask, and stir in a constant temperature heating magnetic stirrer at 80 °C for 1-2 hours. Subsequently, add the iron oxide colloid, ethanol, deionized water, and sodium citrate solution in sequence, and continue magnetic stirring at 80 °C for 1 minute; (3) Then add ammonia water, shake well for 3 minutes, and then add tetraethyl orthosilicate, shake well for 5 minutes, and react at room temperature for 12 hours to grow rod-shaped silicon dioxide around the cubic iron oxide particles.

5. The hexapod cell puncturing micro-nano robot with complex environment adaptability according to claim 4, characterized in that: The process of Step 3 is as follows: Take the obtained reactants to remove the supernatant, add anhydrous ethanol and deionized water in sequence for centrifugation and washing 3 times to obtain a solution containing six-legged micro-nano robots.

6. A dual-mode magnetic drive control device for a six-legged cell puncturing micro-nano robot with complex environmental adaptability according to claim 1, wherein the dual-mode magnetic drive control device includes a microscope (1), a magnetic field generating device, and a gradient magnetic field device (6), characterized in that: The magnetic field generating device uses three groups of Helmholtz coils (2), uses a signal generator as an AC signal source (4) to generate a sine wave signal, amplifies the electrical signal through a power amplifier (3), and inputs it into the Helmholtz coils to generate a uniform magnetic field in any plane in three-dimensional space to drive the six-legged micro-nano robot to rotate along any axis; The main part of the gradient magnetic field device (6) is an electromagnet. A signal generator is used as a DC signal source (5) to generate a stable DC signal. The electrical signal is amplified by a power amplifier (3) and then input into the electromagnet. The electromagnet provides a stable gradient magnetic field perpendicular to the bottom of the cell culture medium in the experimental area, enhancing the vertical movement ability of the hexapod micro-nanorobot. The micro-nanorobot experimental area (7) is located at the exact center of the Helmholtz coil and is supported by the Helmholtz coil.

7. The six-legged cell puncturing micro-nano robot with complex environmental adaptability according to claim 6, 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 due to the magnetic response.

8. The six-legged cell puncture micro-nano robot with complex environment adaptability according to claim 6, characterized in that: The hexapod cell-puncturing micro-nanorobot can rotate along any axis, changing the direction of the uniform rotating magnetic field generated by the Helmholtz coil, enabling precise control of the movement speed and direction of the micro-nanorobot.

9. The six-legged cell puncturing micro-nano robot with complex environment adaptability according to claim 1, characterized in that: The micro-nanorobot has a hexapod structure. During the movement of the hexapod structure on the surface of tissues with complex morphologies, multiple contact fulcrums are generated, facilitating tumbling movement on the surface of tissues with complex morphologies and greatly improving the ability of the micro-nanorobot to adapt to the complex surface morphologies of tissues in vivo.

10. The six-legged cell puncturing micro-nano robot with complex environment adaptability according to claim 6, characterized in that: When the micro-nanorobot tumbles to directly above the cancer cell membrane, the magnetic field generated by the coil is adjusted to a planar rotating magnetic field. The micro-nanorobot is subjected to a magnetic torque in the horizontal plane and rotates at a high frequency around the axis perpendicular to the horizontal plane. At the same time, the gradient magnetic field device (6) at the bottom is turned on, and the micro-nanorobot moves downward under the action of the gradient magnetic force along the direction perpendicular to the bottom of the cell culture medium, while performing rotational movement and linear movement, achieving effective puncture and breakthrough of the cell membrane.

Images