1. A preparation method of a magnetic micro-nano robot is characterized by comprising the following steps:

(1) forming an electron beam photoresist layer on a first substrate, and transferring a pattern on a mask plate to the photoresist layer after exposure and development to obtain a first micro-nano robot hard template;

(2) performing reverse molding on the first micro-nano robot hard template obtained in the step (1) by using a soft reverse molding material to obtain a micro-nano robot soft template;

(3) forming a hard glue layer on a second substrate, and then transferring the pattern on the micro-nano robot soft template to the hard glue layer by adopting a nano-imprinting method to obtain a second micro-nano robot hard template;

(4) and (4) forming a magnetic material layer and a biocompatible material layer on the second micro-nano robot hard template obtained in the step (3), and performing ultrasonic treatment to obtain the magnetic micro-nano robot.

2. The production method according to claim 1, wherein the first substrate in the step (1) is a silicon wafer;

preferably, the thickness of the electron beam photoresist layer in the step (1) is 100-500 nm.

3. The production method according to claim 1 or 2, characterized by further comprising: before the die reversing in the step (2), performing alkylation treatment on the first micro-nano robot hard template;

preferably, the alkylation treatment method is as follows: soaking the first micro-nano robot hard template in an alkylating reagent for 5-12 h;

preferably, the alkylating agent is trimethylchlorosilane.

4. The production method according to any one of claims 1 to 3, wherein the soft reverse molding material in the step (2) is any one of silicone rubber, polymethylsiloxane, polyethylene terephthalate, polybutylene terephthalate, nylon or polycarbonate;

preferably, the method for reverse molding in step (2) is: and placing the first micro-nano robot hard template in a culture dish, adding a precursor solution of the soft reverse mold material, solidifying and then uncovering the formed soft reverse mold material film to obtain the micro-nano robot soft template.

5. The production method according to any one of claims 1 to 4, wherein the second substrate in the step (3) is a silicon wafer;

preferably, the material of the hard glue layer in the step (3) is PMMA or SU-82002;

preferably, the thickness of the hard glue layer is 100-500 nm;

preferably, the thickness of the hard glue layer is greater than that of the magnetic micro-nano robot.

6. The method of any one of claims 1 to 5, wherein the nanoimprinting method is: placing the micro-nano robot soft template and a second substrate with a hard adhesive layer in a nano-imprinting machine, pressurizing at constant temperature to fill the hard adhesive layer material into a cavity of the micro-nano robot soft template, and cooling and then solidifying the pattern;

preferably, the temperature of the nanoimprinting is T_g～T_g+50 ℃ wherein T is_gThe glass transition temperature of the hard glue layer material;

preferably, the nanoimprinting pressure is 2-40 kN.

7. The method for preparing according to any one of claims 1 to 6, wherein the method for forming the magnetic material layer and the biocompatible material layer in step (4) is electron beam evaporation, electron beam sputtering or dual chamber magnetron sputtering, preferably electron beam evaporation;

preferably, the material of the magnetic material layer is selected from one or a combination of at least two of nickel, cobalt or ferroferric oxide;

preferably, the material of the biocompatible material layer is selected from one or a combination of at least two of titanium, platinum, zinc, iron, titanium dioxide or zinc oxide;

preferably, the thickness of the magnetic material layer is 50-130 nm;

preferably, the layer of biocompatible material has a thickness of 10-50 nm.

8. The production method according to any one of claims 1 to 7, characterized by comprising the steps of:

(1) washing the silicon wafer with water, acetone, isopropanol and water in sequence, and drying the silicon wafer with nitrogen to keep the surface of the silicon wafer clean; spin-coating an electron beam photoresist layer with the thickness of 200nm on the surface of the processed silicon wafer at the rotating speed of 2000r/min for 60s, then placing the silicon wafer on a hot plate with the temperature of 90 ℃, and drying for 1-3 min; putting the silicon wafer sample with the electron beam negative adhesive layer into an electron beam exposure machine, and setting the exposure dose to be 800uC/cm²Exposing under a mask plate; placing the exposed silicon wafer sample into an electron beam developing solution for developing for 40-60 s; placing the developed silicon wafer sample on a hot plate at 90 ℃, and drying for 1-2min to obtain a first micro-nano robot hard template;

(2) putting the first micro-nano robot hard template obtained in the step (1) into a trimethylchlorosilane solution, and soaking for 6 hours; taking out a sample, drying the sample by using nitrogen, putting the sample into a culture dish, adding a mixed solution of polymethylsiloxane and a curing agent in a mass ratio of 10:1, then putting the culture dish into a vacuum box, vacuumizing the vacuum box for 2 hours, and then placing the culture dish in an oven at 85 ℃ for 8 hours; taking out a sample from the oven, uncovering a polymethylsiloxane membrane formed after curing from the edge of the culture dish, and performing mould inversion to obtain a micro-nano robot soft template;

(3) spin-coating a PMMA adhesive layer with the thickness of 100nm on a silicon wafer at the rotating speed of 3000r/min for 60s, and then placing the silicon wafer on a hot plate at the temperature of 85 ℃ for baking for 1 min; putting the micro-nano robot soft template obtained in the step (2) and a silicon wafer with a PMMA glue layer into a nano-imprinting machine, setting the nano-imprinting temperature to be 105 ℃, setting the pressure to be 2-40kN, pressurizing at constant temperature, filling the cavity of the micro-nano robot soft template with the flowing PMMA glue, and cooling and then carrying out pattern curing; taking the sample out of the nano-imprinting machine, and uncovering the micro-nano robot soft template by using tweezers to obtain a second micro-nano robot hard template;

(4) and (4) performing electron beam evaporation on the second micro-nano robot hard template obtained in the step (3) to form a nickel metal layer with the thickness of 50-130nm and a titanium metal layer with the thickness of 10-50nm, placing an evaporated sample in water for ultrasonic treatment, collecting a solution after ultrasonic treatment, and filtering to obtain the micro-nano robot.

9. The magnetic micro-nano robot prepared by the preparation method according to any one of claims 1 to 8.

10. The magnetic micro-nano robot of claim 9, in use for preparing in vivo micro target recognition material, targeted drug-loaded material or minimally invasive surgery material.

Background

The micro-nano robot refers to a small robot with the dimension in the micro-nano level (from a few nanometers to a few hundred micrometers), has outstanding advantages in the aspect of solving the problems of assembly and utilization of molecular size devices, and has become a rapidly-developed interdisciplinary field. Based on the advantages that the micro-nano robot is small in size and can perform three-dimensional control movement, the micro-nano robot is applied to in-vivo micro target recognition, targeted drug loading, minimally invasive surgery and the like in the aspect of medicine.

Because the micro-nano robot is small in size and is in an environment with a low Reynolds coefficient when moving, an object can be regarded as moving in a very viscous, small and slow environment, viscous force plays a dominant role, and inertial force can be ignored. Under the condition, if the micro-nano robot is driven, the micro-nano robot must be continuously provided with power. The currently proposed micro-nano robot driving modes comprise self-driving and external field driving. The self-driving means that the micro-nano robot obtains power from the fluid environment to generate motion, and the modes of obtaining power can be divided into self-electrophoresis driving, self-diffusion electrophoresis driving, self-heating electrophoresis driving, bubble driving and the like. The external field driving refers to the movement of the micro-nano robot under the action of an applied external field, and the external field driving mode can be divided into magnetic field driving, sound field driving, optical driving and the like. The magnetic field driving micro-nano robot is low in required magnetic field intensity, and the low-frequency magnetic field can penetrate through biological tissues and is harmless to organisms, so that the magnetic field driving micro-nano robot is a micro-nano robot type with a very promising prospect.

CN 107986230A discloses a preparation method of a patterned bionic magnetic micro-nano robot, which comprises the steps of preparing a polytetrafluoroethylene substrate, a red copper sheet and a porous polycarbonate template; preparing a working electrode; coating photoresist; exposing and developing; preparing an acid electrolyte; wetting the holes of the porous polycarbonate template; preparing a cobalt nanowire and a cobalt substrate; transferring the nanowire and the cobalt substrate; removing the red copper sheet and washing away the porous polycarbonate template; combination with a polytetrafluoroethylene substrate: after the polytetrafluoroethylene substrate and the cobalt nanowire array on one side are formed, the preparation method of the other side is the same, and a double-sided cobalt nanowire array based on the polytetrafluoroethylene substrate is formed; and cutting to obtain the magnetic micro-nano robot. However, the method is complex, and the porous polycarbonate template can only be used for preparing the micro-nano robot once and cannot be reused.

The Nelson topic group (Tottori S, Zhang L, Qiu F, et al. magnetic thermal micro-robots: Fabrication, controlled swamming, and cargo transport. adv Mater,2012,24: 811-. Under the action of an external rotating uniform magnetic field, the spiral propulsion type robot can reach the movement speed of 180 mu m/s in water. However, the laser direct writing cost is high, the efficiency is low, and the smaller the size of the prepared micro-nano robot is, the lower the efficiency is, and the micro-nano robot is difficult to prepare on a large scale.

Therefore, a method which is low in cost and can rapidly prepare the micro-nano robot in a large scale needs to be researched in the field.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a preparation method and application of a magnetic micro-nano robot. Compared with the existing laser direct writing method, the preparation method provided by the invention has lower cost, and can be used for rapidly preparing the magnetic micro-nano robot in large batch.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a preparation method of a magnetic micro-nano robot, which comprises the following steps:

(1) forming a photoresist layer on a first substrate, and transferring a pattern on a mask plate to the photoresist layer after exposure and development to obtain a first micro-nano robot hard template;

(2) performing reverse molding on the first micro-nano robot hard template obtained in the step (1) by using a soft reverse molding material to obtain a micro-nano robot soft template;

(3) forming a hard glue layer on a second substrate, and then transferring the pattern on the micro-nano robot soft template to the hard glue layer by adopting a nano-imprinting method to obtain a second micro-nano robot hard template;

(4) and (4) forming a magnetic material layer and a biocompatible material layer on the second micro-nano robot hard template obtained in the step (3), and performing ultrasonic treatment to obtain the magnetic micro-nano robot.

It should be noted that the first micro-nano robot hard template and the second micro-nano robot hard template are convex plates, and the shape of the prepared magnetic micro-nano robot is the same as the template pattern. For the template pattern, a person skilled in the art can select the template pattern as required, as long as the micro-nano robot in the shape can move under the action of a magnetic field.

According to the invention, a second micro-nano robot hard template can be repeatedly prepared from a micro-nano robot soft template by adopting a nano imprinting method, then a magnetic material layer and a biocompatible material layer are formed on the second micro-nano robot hard template, the magnetic material layer and the biocompatible material layer on the template graph are separated by ultrasonic vibration to form a two-dimensional micro-nano robot, and the magnetic material layer and the biocompatible material layer outside the template graph area are firmly combined and cannot fall off due to large areas. Compared with the existing laser direct writing method, the preparation method provided by the invention has the advantages of lower cost and higher preparation efficiency, and can be used for preparing the micro-nano robot in a large scale.

As a preferred embodiment of the present invention, in the step (1), the first substrate is a silicon wafer.

Preferably, the thickness of the electron beam resist layer in step (1) is 100-500nm, such as 100nm, 150nm, 200nm, 250nm, 300nm, 350nm, 400nm, 450nm or 500 nm.

The present invention is not particularly limited to the kind of the photoresist, and those skilled in the art can select the photoresist according to the need, and can exemplarily select the electron beam photoresist or the ultraviolet photoresist. Generally, the electron beam glue has higher exposure precision and can be used for preparing a nano robot; the ultraviolet photoresist has lower exposure precision and can be used for preparing a micron robot.

As a preferred embodiment of the present invention, the preparation method further comprises: and (3) before the die reversing in the step (2), performing alkylation treatment on the first micro-nano robot hard template.

In the invention, the alkylation treatment is carried out to reduce the adhesion of the first micro-nano robot hard template so as to facilitate the separation of the hard template and the soft template after the reverse mould.

Preferably, the alkylation treatment method is as follows: and soaking the first micro-nano robot hard template in an alkylation reagent for 5-12h, such as 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12 h.

Preferably, the alkylating agent is trimethylchlorosilane.

In a preferred embodiment of the present invention, in the step (2), the soft reverse mold material is any one of silicone rubber, Polymethylsiloxane (PDMS), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), nylon (PA), and Polycarbonate (PC).

Preferably, the method for reverse molding in step (2) is: and placing the first micro-nano robot hard template in a culture dish, adding a precursor solution of the soft reverse mold material, solidifying and then uncovering the formed soft reverse mold material film to obtain the micro-nano robot soft template.

As a preferred embodiment of the present invention, in the step (3), the second substrate is a silicon wafer.

Preferably, the material of the hard glue layer in the step (3) is PMMA or SU-82002.

Preferably, the thickness of the hard glue layer is 100-500nm, such as 100nm, 150nm, 200nm, 250nm, 300nm, 350nm, 400nm, 450nm or 500 nm.

Preferably, the thickness of the hard glue layer is greater than that of the magnetic micro-nano robot.

As a preferred technical solution of the present invention, the nanoimprinting method includes: and placing the micro-nano robot soft template and a second substrate with a hard adhesive layer in a nano-imprinting machine, pressurizing at constant temperature to enable the hard adhesive layer material to be filled in a cavity of the micro-nano robot soft template, and cooling and then solidifying the pattern.

Preferably, the temperature of the nanoimprinting is T_g～T_g+50 ℃ wherein T is_gThe glass transition temperature of the hard glue layer material.

Preferably, the nanoimprint pressure is 2-40 kN; for example, 2kN, 3kN, 5kN, 8kN, 10kN, 15kN, 20kN, 25kN, 30kN, 35kN, 40kN, etc.

As a preferred embodiment of the present invention, the method for forming the magnetic material layer and the biocompatible material layer in step (4) is electron beam evaporation, electron beam sputtering or dual-chamber magnetron sputtering, and preferably electron beam evaporation.

In a preferred embodiment of the present invention, the material of the magnetic material layer is selected from one or a combination of at least two of nickel, cobalt, and ferroferric oxide.

Preferably, the material of the biocompatible material layer is selected from one or a combination of at least two of titanium, platinum, zinc, iron, titanium dioxide or zinc oxide.

The nickel and titanium are low in cost, and the nickel-titanium alloy has good biocompatibility in a human body, so that the application potential of the nano robot in the human body can be increased. By further modifying the surface of the nano robot with functional groups, the nano robot can be used for carrying and releasing various medicines.

As a preferred technical scheme of the invention, the thickness of the magnetic material layer is 50-130 nm; for example, it may be 50nm, 55nm, 60nm, 65nm, 70nm, 75nm, 80nm, 85nm, 90nm, 95nm, 100nm, 105nm, 110nm, 115nm, 120nm, 125nm or 130 nm.

Preferably, the thickness of the biocompatible material layer is 10-50 nm; for example, it may be 10nm, 15nm, 20nm, 25nm, 30nm, 35nm, 40nm, 45nm or 50 nm.

As a preferred technical scheme of the invention, the preparation method comprises the following steps:

(1) washing the silicon wafer with water, acetone, isopropanol and water in sequence, and drying the silicon wafer with nitrogen to keep the surface of the silicon wafer clean; spin-coating an electron beam photoresist layer with the thickness of 200nm on the surface of the processed silicon wafer at the rotating speed of 2000r/min for 60s, then placing the silicon wafer on a hot plate with the temperature of 90 ℃, and drying for 1-3 min; putting the silicon wafer sample with the electron beam negative adhesive layer into an electron beam exposure machine, and setting the exposure dose to be 800uC/cm²Exposing under a mask plate; placing the exposed silicon wafer sample into an electron beam developing solution for developing for 40-60 s; placing the developed silicon wafer sample on a hot plate at 90 ℃, and drying for 1-2min to obtain a first micro-nano robot hard template;

(2) putting the first micro-nano robot hard template obtained in the step (1) into a trimethylchlorosilane solution, and soaking for 6 hours; taking out a sample, drying the sample by using nitrogen, putting the sample into a culture dish, adding a mixed solution of PDMS and a curing agent in a mass ratio of 10:1, then putting the culture dish into a vacuum box, vacuumizing the vacuum box for 2 hours, and then placing the culture dish in an oven at 85 ℃ for 8 hours; taking out a sample from the oven, uncovering a PDMS film formed after curing from the edge of the culture dish, and performing mould inversion to obtain a micro-nano robot soft template;

(3) spin-coating a PMMA adhesive layer with the thickness of about 100nm on a silicon wafer at the rotating speed of 3000r/min for 60s, and then placing the silicon wafer on a hot plate at the temperature of 85 ℃ for baking for 1 min; putting the micro-nano robot soft template obtained in the step (2) and a silicon wafer with a PMMA glue layer into a nano-imprinting machine, setting the nano-imprinting temperature to be 105 ℃, setting the pressure to be 2-40kN, pressurizing at constant temperature, filling the cavity of the micro-nano robot soft template with the flowing PMMA glue, and cooling and then carrying out pattern curing; taking the sample out of the nano-imprinting machine, and uncovering the micro-nano robot soft template by using tweezers to obtain a second micro-nano robot hard template;

(4) and (4) performing electron beam evaporation on the second micro-nano robot hard template obtained in the step (3) to form a nickel metal layer with the thickness of 50-130nm and a titanium metal layer with the thickness of 10-50nm, placing an evaporated sample in water for ultrasonic treatment, collecting a solution after ultrasonic treatment, and filtering to obtain the micro-nano robot.

On the other hand, the invention provides the application of the magnetic micro-nano robot in preparing in-vivo micro target recognition materials, targeted drug-loaded materials or minimally invasive surgery materials.

Compared with the prior art, the invention has the following beneficial effects:

according to the invention, a high-precision micro-nano processing technology of nanoimprint is applied to the preparation of the micro-nano robot, and a second micro-nano robot hard template can be repeatedly and rapidly prepared by a micro-nano robot soft template for multiple times, so that the mass preparation of micro-nano level robots becomes possible, and the high precision of 20nm level is reached. Compared with the existing laser direct writing method, the preparation method provided by the invention has the advantages of lower cost and higher preparation efficiency, and the soft template can be repeatedly utilized, so that the preparation method is suitable for preparing the micro-nano robot on a large scale.

Drawings

Fig. 1 is a scanning electron microscope photograph of the nano-robot provided in embodiment 1 of the present invention, with a scale of 200 nm.

Fig. 2 is a scanning electron microscope photograph of the nano-robot provided in embodiment 2 of the present invention, with a scale of 200 nm.

Fig. 3 is a scanning electron microscope photograph of the nano-robot provided in embodiment 3 of the present invention, with a scale of 200 nm.

Detailed Description

The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached drawings. It should be understood by those skilled in the art that the specific embodiments are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

The raw materials used in the examples of the invention were sourced as follows:

electron beam negative resist: AR N-7520.07 from Microchem, USA;

PDMS and curing agents-dow corning 184: shenzhen Tainuodi science and technology Limited

PMMA glue: merck of America

Example 1

The embodiment provides a preparation method of a nano robot, which comprises the following steps:

(1) washing the silicon wafer with water, acetone, isopropanol and water in sequence, and drying the silicon wafer with nitrogen to keep the surface of the silicon wafer clean; spin-coating an electron beam negative adhesive layer with the thickness of 200nm on the surface of the processed silicon wafer at the rotating speed of 2000r/min for 60s, then placing the silicon wafer on a hot plate with the temperature of 90 ℃, and drying for 1 min; putting the silicon wafer sample with the electron beam negative adhesive layer into an electron beam exposure machine, and setting the exposure dose to be 800uC/cm²Exposing under a mask plate; placing the exposed silicon wafer sample into an electron beam developing solution for developing for 40 s; placing the developed silicon wafer sample on a hot plate at 90 ℃, and drying for 1min to obtain a first micro-nano robot hard template (the template graph is in a convex L shape);

(2) putting the first micro-nano robot hard template obtained in the step (1) into a trimethylchlorosilane solution, and soaking for 6 hours; taking out a sample, drying the sample by using nitrogen, putting the sample into a culture dish, adding a mixed solution of PDMS and curing agent Dow Corning 184 in a mass ratio of 10:1, then putting the culture dish into a vacuum box, vacuumizing the vacuum box for 2 hours, and then placing the culture dish in an oven at 85 ℃ for 8 hours; taking out a sample from the oven, uncovering a PDMS film formed after curing from the edge of the culture dish, and performing reverse molding to obtain a micro-nano robot soft template (the template pattern is a concave L shape);

(3) spin-coating a PMMA adhesive layer with the thickness of 100nm on a silicon wafer at the rotating speed of 3000r/min for 60s, and then placing the silicon wafer on a hot plate at the temperature of 85 ℃ for baking for 1 min; putting the micro-nano robot soft template obtained in the step (2) and a silicon wafer with a PMMA glue layer into a nano-imprinting machine, setting the nano-imprinting temperature to be 105 ℃, setting the pressure to be 10kN, pressurizing at constant temperature, filling the cavity of the micro-nano robot soft template with the flowing PMMA glue, and cooling and then carrying out pattern curing; taking out the sample from the nano-imprinting machine, and uncovering the micro-nano robot soft template by using tweezers to obtain a second micro-nano robot hard template (the template graph is in a convex L shape);

(4) and (4) performing electron beam evaporation on the second micro-nano robot hard template obtained in the step (3) to form a nickel metal layer with the thickness of 80nm and a titanium metal layer with the thickness of 20nm, placing the evaporated sample in water for ultrasonic treatment, collecting the solution after ultrasonic treatment, and filtering to obtain the nano robot.

The nanotechnology obtained in this example was characterized by using a scanning electron microscope (FEI, model: Nova NanoSem 450), and as a result, it can be seen that the nanotechnology is "L" shaped, with a long side of 1 μm and a short side of 0.3. mu.m, as shown in FIG. 1.

Example 2

This example provides a method for preparing a nano robot, which is different from example 1 in that the template pattern is "C" shaped, and a cobalt metal layer having a thickness of 50nm and a platinum metal layer having a thickness of 10nm are electron beam evaporated in step (4).

The nano robot obtained in this example was characterized by using a scanning electron microscope, and as a result, as shown in fig. 2, it can be seen that the nano robot is "C" shaped, and the width of the ring is 0.3 μm.

Example 3

The embodiment provides a preparation method of a nano robot, which is different from the embodiment 1 in that a template pattern is in a shape of 'angle', and a ferric oxide layer with the thickness of 130nm and a titanium dioxide layer with the thickness of 50nm are evaporated by an electron beam in the step (4).

The nano-robot obtained in the present embodiment is characterized by using a scanning electron microscope, and the result is shown in fig. 3, which shows that the nano-robot is shaped like an "angle", the long side is 1 μm, and the short side is 0.3 μm.

The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.