CN119184801A - Micron-sized magnetic control cell micro-clamp system for medical detection and diagnosis - Google Patents
Micron-sized magnetic control cell micro-clamp system for medical detection and diagnosis Download PDFInfo
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Abstract
The application discloses a micron-sized magnetic control cell micro-clamp system for medical detection and diagnosis, and relates to the technical field of detection and diagnosis. Can realize stable and controllable cell grabbing, triggering release and transportation in the in-vivo and in-vitro environment, and provides an important tool for automatic accurate diagnosis and clinical detection of cell-related diseases. The system comprises a micron-sized magnetic control cell micro-clamp, an in-vitro magnetic control system and an in-vivo magnetic control system, wherein the in-vitro magnetic control system can generate a first external magnetic field for driving the micron-sized magnetic control cell micro-clamp to perform cell operation in vitro, the in-vivo magnetic control system can generate a second external magnetic field for driving the micron-sized magnetic control cell micro-clamp to perform cell transportation operation in vivo, the micron-sized magnetic control cell micro-clamp comprises two clamp bodies and an elastic piece, the clamp bodies are formed by processing super-elastic photoresist materials doped with superparamagnetic materials, and the clamp bodies can be opened or closed under the action of the first external magnetic field or the second external magnetic field so as to grasp or release cells.
Description
Technical Field
The application relates to the technical field of medical detection and diagnosis, in particular to a micrometer-scale magnetic control cell micro-clamp system for medical detection and diagnosis.
Background
Along with the development of micro-nano robot technology, how to accurately operate single cells or cell clusters on a micron scale, so that the micro-nano robot technology is used for medical detection and diagnosis, and becomes an important research direction of biomedical engineering. The conventional mechanical method is difficult to meet the requirements of precision and flexibility of cell operation. Furthermore, a key issue in cell manipulation is how to fix fragile target cells firmly enough without applying damaging pressure thereto. Current micro-robotics generally immobilize transported biological cells and tissues by designing microstructures such as micro-clamps or micro-coils that capture the cells. However, the conventional microstructure mostly adopts a static non-closed cell compartment structure, for example, a cylindrical structure with one end opened, and has a disadvantage in that the cells are easily removed during transportation. The magnetic control technology gradually becomes an ideal choice for cell manipulation due to the advantages of no contact, high precision and remote control. In addition, the existing magnetic control micro-operation system often lacks integration and systemization, and cannot be simultaneously applied to complex operation environments in vivo and in vitro. Therefore, a micron-sized magnetic control cell micro-clamp system with high integration level, high instantaneity and high applicability is developed, and the research value and the application prospect are important.
Disclosure of Invention
The embodiment of the application provides a micron-sized magnetic control cell micro-clamp system for medical detection and diagnosis, which can realize stable and controllable cell grabbing, triggering release and transportation in the in-vitro environment and provides an important tool for automatic accurate diagnosis and clinical detection of cell-related diseases.
In order to achieve the above purpose, the embodiment of the application provides a micrometer magnetic control cell micro-clamp system for medical detection and diagnosis, which comprises a micrometer magnetic control cell micro-clamp, an in-vitro magnetic control system and an in-vivo magnetic control system, wherein the in-vitro magnetic control system can generate a first external magnetic field for driving the micrometer magnetic control cell micro-clamp to perform cell operation in vitro, the in-vivo magnetic control system can generate a second external magnetic field for driving the micrometer magnetic control cell micro-clamp to perform cell transportation operation in vivo, the micrometer magnetic control cell micro-clamp comprises two clamp bodies and an elastic piece, the two clamp bodies are oppositely arranged, the elastic piece can restrict the two clamp bodies to a clamp opening state, the clamp bodies are formed by processing super-elastic photoresist material doped with superparamagnetic material, and the clamp bodies can be opened or closed under the action of the first external magnetic field or the second external magnetic field so as to grab or release cells and transport the cells to a preset position.
Further, when the clamp body is in a closed state, the single cells can be clamped in the jaws.
Further, the clamp body is a serrated clamp body or a claw-shaped clamp body.
Further, the head-tail direction of the clamp body is an easy magnetization axis.
The micro-scale magnetic control cell micro-clamp is driven to roll and open when the first external magnetic field is converted into the rotating uniform magnetic field with the magnetic field strength being more than 7mT, the micro-scale magnetic control cell micro-clamp is driven to roll and close when the first external magnetic field is converted into the rotating uniform magnetic field with the magnetic field strength being less than 7mT, and the micro-scale magnetic control cell micro-clamp is driven to roll and open when the first external magnetic field is converted into the gradient magnetic field with the gradient of 0-1T/m or when the second external magnetic field is converted into the gradient magnetic field with the gradient of 0-5T/m.
Further, an included angle is formed between the two clamp bodies, and the easy axis of magnetization can be deflected by controlling the intensity of the first external magnetic field and the second external magnetic field, so that the size of the included angle between the two clamp bodies is controlled.
The in-vitro magnetic control system comprises a three-dimensional Helmholtz coil, a first data acquisition card, a first power amplifier, a first relay, a first computer and a cell detection module, wherein the three-dimensional Helmholtz coil and the cell detection module are arranged on a bearing bracket, a sample platform is arranged at the center of the three-dimensional Helmholtz coil and used for placing a culture dish for culturing cells to be operated, the cell detection module is in communication connection with the first computer and can monitor living tissues and cells and monitor the positions of micro-magnetic control cell micro-clamps in real time, the first data acquisition card is in communication connection with the first computer, the first relay is in electric connection with the three-dimensional Helmholtz coil, the signal input end of the first power amplifier is connected with the analog signal output end of the first data acquisition card, and the output end of the first power amplifier is connected with the power input end of the first relay.
The cell detection module comprises an optical biological microscope and a microscope camera, wherein the optical biological microscope is an inverted fluorescent microscope, an objective lens is inverted below a sample platform, and the microscope camera is connected with a trinocular port of the optical biological microscope to realize the butt joint of the microscope camera and an optical system of the optical biological microscope.
The in-vivo magnetic control system comprises a magnetic field generator, a scanning bed, an OCT imaging system, a second computer, a second data acquisition card, a second power amplifier and a second relay, wherein the magnetic field generator comprises a body and a plurality of groups of superconducting electromagnet coils which are arranged on the body along the X, Y, Z axis direction, the body is of a ring-shaped or cylindrical structure which can be used for a patient to pass through, the OCT imaging system can detect the position of a micrometer-scale magnetic control cell micro clamp in the body in real time, the second data acquisition card is in communication connection with the second computer, the second relay is in electric connection with the superconducting electromagnet coils, the signal input end of the second power amplifier is connected with the analog signal output end of the second data acquisition card, and the output end of the second power amplifier is connected with the power input end of the second relay.
Compared with the prior art, the application has the following beneficial effects:
1. The clamp body of the micron-sized magnetic control cell micro clamp is processed by adopting super-elastic photoresist material doped with super-paramagnetic material, and the clamp body has larger aspect ratio, and the two clamp bodies are connected through the elastic piece, so that after a weak rotating magnetic field is applied to the micro clamp through an in-vitro or in-vivo magnetic control system, the micro clamp is in a closed state and is turned towards a target cell due to the constraint of the elastic piece. When the micro-clamp reaches the target position, a strong rotating magnetic field is applied, and the head and tail directions of the clamp body are easy to magnetize, so that the clamp body can be aligned with the directions of the strong magnetic field, at the moment, the clamp body overcomes the resistance of the elastic piece to rotate, the micro-clamp is in an open state, after cells enter the clamp jaw, the strength of the strong magnetic field is reduced, the micro-clamp clamps the cells and transfers the cells to a preset position, and as the micro-clamp is controlled to open and close and drive by the magnetic field, stable cell transportation and triggering release can be realized, and the micro-clamp can be used for grabbing cells or other objects with different geometric shapes and sizes by adjusting the opening and closing deformation amplitude of the micro-clamp.
2. The embodiment of the application can not only finish cell operation in a laboratory environment, but also perform fine micro-operation in a complex biological environment in vivo by combining in-vitro and in-vivo magnetic control systems. The double system design greatly expands the application scene of the micro clamp, so that the micro clamp is not only suitable for single cell operation in vitro experiments, such as accurate control of cell behavior in a culture dish, but also can carry out complex operations such as cell grabbing, transportation and the like in vivo, such as blood vessels or other body lumen tracts.
3. The integrated optical microscope and OCT imaging system provides real-time visual feedback for the operation of the micron-sized magnetic control cell micro clamp, so that researchers can accurately monitor the movement states of the cell and the micro clamp, and the accuracy and the safety of the operation are ensured. The embodiment of the application not only brings new possibility for biomedical research and clinical biological diagnosis, but also provides wide prospect for application in the fields of minimally invasive surgery, drug delivery and the like.
Drawings
In order to more clearly illustrate the embodiments of the application or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the application and that other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic structural diagram of embodiment 1 of the present application;
FIG. 2 is a front view of a micro-gripper for micro-magnetic control cells according to example 1 of the present application;
FIG. 3 is a top view of a micro-clamp for micro-scale magnetically controlled cells according to example 1 of the present application;
FIG. 4 is a closed state diagram of a micro-clamp for micro-magnetic control cells according to example 1 of the present application;
FIG. 5 is a diagram showing the open state of the micro-clamp for micro-magnetic control cells according to example 1 of the present application;
FIG. 6 is a diagram showing the state of clamping the micro-clamp for micro-magnetic control cells according to example 1 of the present application;
FIG. 7 is a schematic diagram of the external magnetic control system in embodiment 1 of the present application;
FIG. 8 is a diagram showing the image detected by the cell detection module in example 1 of the present application;
FIG. 9 is a schematic diagram of the in vivo magnetic control system in embodiment 1 of the present application;
FIG. 10 is an image detected by the OCT imaging system of embodiment 1 of the present application;
FIG. 11 is a front view of a micro-gripper for micro-magnetic control cells according to example 2 of the present application;
FIG. 12 is a top view of a micro-clamp for micro-magnetic control cells of example 2 of the present application.
Detailed Description
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
In the description of the present application, it should be understood that the terms "center," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," "outer," and the like indicate orientations or positional relationships based on the orientation or positional relationships shown in the drawings, merely to facilitate describing the present application and simplify the description, and do not indicate or imply that the devices or elements referred to must have a specific orientation, be configured and operated in a specific orientation, and thus should not be construed as limiting the present application.
In the description of the present application, it should be noted that, unless explicitly specified and limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, and for example, can be either fixedly connected, detachably connected, or integrally connected, and that the specific meaning of the terms in the present application can be understood as specific to one of ordinary skill in the art.
The terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first", "a second" can explicitly or implicitly include one or more such feature. In the description of the present application, unless otherwise indicated, the meaning of "a plurality" is two or more.
Example 1:
Referring to fig. 1, the present application provides a micro-magnetic control cell micro-clamp system for medical detection and diagnosis, comprising a micro-magnetic control cell micro-clamp 10, an in-vitro magnetic control system 20 and an in-vivo magnetic control system 30. The in vitro magnetic control system 20 is capable of generating a first external magnetic field that drives the micro-scale magnetic control cell micro-clamp to perform cell manipulation in vitro. The in-vivo magnetic control system 30 is capable of generating a second external magnetic field that drives the micro-scale magnetic control cell micro-clamp to perform cell transport operations in the body.
Referring to fig. 2 to 6, the micro-magnetic control cell micro-clamp 10 includes two clamp bodies 1 disposed opposite to each other and an elastic member 2 connected between the clamp bodies 1. The elastic member 2 is capable of restraining the two clamp bodies 1 in the jaw closed state. The clamp body 1 is formed by processing super-elastic photoresist material doped with superparamagnetic material. The clamp body 1 can be opened or closed under the action of a first external magnetic field or a second external magnetic field to grasp or release the cells 3 and transport the cells 3 to a preset position.
The first external magnetic field is generated by the external magnetic control system 20. The first external magnetic field is a variable magnetic field that can be switched between a rotating uniform magnetic field and a gradient magnetic field, and the magnetic field strength of the rotating uniform magnetic field is variable. When the magnetic field strength of the rotating uniform magnetic field is 15mT, the clamp body 1 can be driven to roll and advance and open to grasp or release the cells, and when the magnetic field strength of the rotating uniform magnetic field is 5mT, the clamp body 1 can be driven to roll and advance and close to transport the cells to a preset position. For convenience of description, a magnetic field having a magnetic field strength of 15mT will be hereinafter referred to as a strong magnetic field, and a magnetic field having a magnetic field strength of 5mT will be hereinafter referred to as a weak magnetic field.
The gradient magnetic field is a gradient magnetic field with the gradient of 0-1T/m.
The second external magnetic field is generated by the in vivo magnetic control system 30. The second external magnetic field is a variable magnetic field that can be switched between a rotating uniform magnetic field and a gradient magnetic field, and the magnetic field strength of the rotating uniform magnetic field is variable. When the magnetic field strength of the rotating uniform magnetic field is 15mT, the clamp body 1 can be driven to roll and advance and open to grasp or release the cells, and when the magnetic field strength of the rotating uniform magnetic field is 5mT, the clamp body 1 can be driven to roll and advance and close to transport the cells to a preset position. The gradient magnetic field is a gradient magnetic field with a gradient of 0-5T/m.
The clamp body 1 contains a magnetic material, when an external magnetic field is applied, the clamp body 1 has a magnetic moment, and the clamp body 1 has a large aspect ratio in structure, and after the clamp body is placed in the magnetic field, the length direction (head-tail direction) of the clamp body 1 is an easy magnetization axis and is aligned with the direction of a strong magnetic field.
The clamp body 1 is a saw tooth clamp body. A jaw is formed between the two clamp bodies 1, and grabbing teeth 11 are arranged on the inner sides of the jaws. The grasping teeth 11 can prevent the fine objects (such as sperm) from slipping out when grasping, and can restrict the grasping objects within the jaws. Normally, the jaw of the micro-clamp is closed by being restrained by the elastic piece 2, and the included angle between the two clamp bodies 1 is an acute angle during closing. The included angle between the two clamp bodies 1 can be controlled by controlling the strength of the rotating uniform magnetic field. That is, when an external strong magnetic field is applied, the two clamp bodies 1 are aligned with the direction of the external magnetic field, the included angle between the two clamp bodies is reduced to be close to zero, and the micro clamp is in an open state, that is, the two clamp bodies are parallel to each other, and the distance between the two clamp bodies is larger than the diameter of the cell 3. After the intensity of the external magnetic field is reduced, the jaws tend to be closed under the action of the elastic piece 2, and the micro-clamp is in a clamping state, so that single cells 3 can be clamped in the jaws, and the loss of the cells 3 in the movement process of the micro-clamp is avoided.
The elastic piece 2 is made of a low elastic modulus photoresist material doped with a superparamagnetic material, has the characteristics of low rigidity and high elastic deformation, and can ensure that the micro-clamp can not damage cells 3 in the opening and closing processes.
Referring to fig. 1, 7 and 8, the in vitro magnetic control system 20 is a high precision magnetic field control system for generating and controlling a three-dimensional alternating magnetic field, thereby precisely controlling the movement and operation of the micro-clamp. The in vitro magnetic control system 20 comprises a three-dimensional helmholtz coil 21, a first data acquisition card 22, a first power amplifier 23, a first relay (not shown in the figure), a first computer, a cell detection module and a sample platform 291. The first computer comprises a first computer host 24 and a first computer display 25. The cell detection module includes an optical biological microscope 26, a microscope camera 27, and a microscopic light source 28. The optical biological microscope 26 is a fluorescence microscope.
The three-dimensional helmholtz coil 21 can generate a stable three-dimensional alternating magnetic field. The alternating frequency range can be adjusted to be 0-30Hz so as to adapt to different experimental requirements. When generating a uniform magnetic field, the coil system can provide magnetic field intensity of up to 20mT in a central area, the uniform magnetic field ensures uniform distribution of the field, and the micro-nano paramagnetic structure in the magnetic field is driven to directionally rotate by generating moment action, and when generating a gradient magnetic field, the magnetic field gradient can reach 1T/m, compared with the gradient magnetic field, the gradient magnetic field can apply translation force by generating magnetic force gradient, so that the micro-nano paramagnetic structure is driven to realize linear displacement. Specifically, the three-dimensional helmholtz coil 21 is composed of three coils arranged in an orthogonal manner, and controls the magnetic fields in three directions X, Y and Z, respectively. Each coil is composed of an inner layer coil and an outer layer coil. The diameter of the inner ring of the X-axis coil group is 24cm, and the diameter of the outer ring is 30cm. The diameter of the inner ring of the Y-axis coil group is 18cm, and the diameter of the outer ring is 24cm. The diameter of the inner ring of the Z-axis coil group is 12cm, and the diameter of the outer ring is 18cm.
To ensure that the central region produces a uniform magnetic field, the three-dimensional helmholtz coil 21 is arranged on a load-bearing support 29. The bearing support 29 has a height adjusting function, and can manually adjust the position of the coil according to the requirement, and the height adjustable range is 20cm.
The first relay and three of the three-dimensional helmholtz coils 21 are electrically connected by wires. The signal input end of the first power amplifier 23 is connected with the analog signal output end of the first data acquisition card 22, and the output end of the first power amplifier 23 is connected with the power input end of the first relay through a connecting wire. The first data acquisition card 22 is connected with the first computer through a USB communication interface. The first computer is in communication connection with the cell detection module and displays the detection result of the cell detection module.
The first data acquisition card 22 is capable of outputting an analog signal according to preset magnetic field parameters. The preset magnetic field parameters are entered by the operator via the first computer. Specifically, the first data acquisition card 22 has six-channel synchronous analog output, supports multi-channel synchronous control, can accurately adjust the voltage intensity, waveform and frequency of the six helmholtz coils, and has an output range of ±10v, thereby realizing omnibearing control of magnetic field parameters.
The first power amplifier 23 can amplify the power of the analog signal output by the first data acquisition card 22 and convert the analog signal into a current value required for driving the coil, so as to ensure that the coil generates a required magnetic field intensity.
The first relay is configured to be capable of electrically switching the current direction of each coil, and the circuit switch of the relay is changed by adjusting the digital signal level (high level or low level) of the output of the acquisition card, so that the current flow direction through the coils is converted, the direction and the property of the magnetic field are flexibly changed, and a uniform magnetic field or a gradient magnetic field is generated by switching.
The magnitude of the current is indirectly determined by a signal input by the first computer to the first data acquisition card 22. The first data acquisition card 22 converts the acquired computer signal into an analog signal for output, and adjusts the current of the three-dimensional helmholtz coil 21. Specifically, the first computer serves as a control center of the system, runs a control program, communicates with the first data acquisition card 22 through a USB interface, and adjusts parameters of an output signal in real time. The first computer can accurately control the frequency, intensity, waveform and other key parameters of the magnetic field, and the image feedback image of the microscope in the cell detection module is monitored and adjusted in real time so as to realize high-precision control and path planning of the micro-clamp operation.
To facilitate manipulation and observation of the sample, a sample platform 291 is provided in the central region of the three-dimensional helmholtz coil 21. Specifically, the sample platform 291 is located at the center of the two coils in the Z-axis, which facilitates the adjustment of the movement of the sample in the XY-axis. The coil is internally provided with a triaxial Hall sensor (not shown in the figure), and the signal output end of the sensor is electrically connected with the analog signal input end of the acquisition card through a lead.
A culture dish for culturing cells to be handled is placed on the sample stage 291. Sample platform 291 is 10cm long and wide and is made of a low permeability material to minimize interference with the magnetic field. The sample stage 291 is composed of a fine adjustment stage, supports electric movement in three directions of XYZ, and has a repeated positioning accuracy of ±2 μm. Through the fine tuning function of the platform, the sample can be accurately positioned under the microscope, so that the operation and observation are convenient. The sample platform also carries a sample tray, and the adapted model can be replaced according to the size of the sample culture dish.
The optical biological microscope 26, the microscope camera 27 and the microscopic light source 28 are also mounted on a load-bearing support 29. The optical biological microscope 26 is an inverted fluorescence microscope with the objective lens inverted below the sample platform. The microscope camera 27 is connected with the three-eye port of the optical biological microscope 26 to realize the butt joint of the camera and the optical system of the microscope.
The microscope stand has stability and flexibility that allows the microscope to be operated at different heights and angles to accommodate different viewing requirements. The optical biomicroscope 26 is equipped with multiple sets of lenses, and the user can switch between 4X, 10X, 20X, 40X and 63X magnifications by rotating the lens converter to adjust the level of detail of the observation as desired. The microscope uses a fluorescent light source that excites fluorescent dyes in the sample so that cells or other biological samples are clearly visible under the microscope.
The microscope camera 27 has high resolution imaging capability, and resolution is up to 4096×2160 pixels (4K UHD), so that fine details of cells can be captured, and definition of images can be ensured. The signal output of the microscope camera 27 is connected to the signal input of the first computer via a USB communication interface. At the same time, the microscope camera 27 also supports high frame rate shooting, and in 1080p full high definition mode, the frame rate can reach 60 frames/second. The high frame rate supports real-time dynamic observation of micro-clamp and cell activity in the culture dish, can capture the rapidly-changed cell behavior, and improves the detection accuracy and reliability. Thus, the cell detection module can monitor living tissues and cells in an in vitro environment and monitor the position of the micrometer-scale magnetic control cell micro-clamp 10 in real time.
Referring to fig. 1 and 9, the in-vivo magnetic control system 30 is a magnetic control system similar to an MR machine, and is specifically designed for human body passing and high-precision magnetic field manipulation. The in-vivo magnetic control system 30 includes a magnetic field generator 31, a scanning bed 32, an OCT imaging system 33, a second computer 34, a second data acquisition card 35, a second power amplifier 36, and a second relay 37. The magnetic field generator 31 includes a body 311 and a plurality of sets of superconducting electromagnet coils 312 provided on the body 311.
The body 311 has a ring-shaped or cylindrical structure through which a patient scanning bed can pass, and is made of a material having excellent magnetic shielding properties, ensuring the safety of a human body and the concentration of a magnetic field during operation. Specifically, in order to adapt to the human body to pass through, the diameter of the system channel is 80cm, the length is 2.5 meters, and the inner wall of the channel is covered by medical silica gel flexible materials, so that the safety in the passing process is ensured. The human body positioning device is arranged in the channel, so that accurate positioning in the operation process is ensured. In order to ensure safety, the system shell adopts high-efficiency magnetic shielding materials to prevent the magnetic field from leaking, and is provided with an emergency stop device and a monitoring alarm system to monitor the state of the magnetic field in real time.
The superconducting electromagnet coils 312 are composed of superconducting magnets that are capable of generating a high-strength, stable magnetic field under the influence of a liquid coolant such as liquid helium or liquid nitrogen. The sets of superconducting electromagnet coils 312 are arranged along the X, Y, Z axis. Specifically, superconducting electromagnet coil 312 includes an X-axis magnetic control coil, a Z-axis magnetic control coil, and a Y-axis magnetic control coil, and precise control of the three-dimensional magnetic field can be achieved. The magnetic field intensity can be adjusted within the range of 0.1T to 3T, and the maximum magnetic field gradient can reach 5T/m, so that the accurate positioning and control of the magnetic micro clamp or micro device in the human body can be realized. Each electromagnetic coil of the in-vivo magnetic control system 30 is made of a high-conductivity copper wire and is supplied with power by a high-voltage ac power supply. The second relay 37 is used to regulate the magnitude and direction of the current of the solenoid. The electromagnetic coils are connected in parallel to ensure the uniformity and strength of the magnetic field. The dimensions of each electromagnetic coil are precisely designed to ensure that the required strong magnetic field can be generated. To prevent overheating, cooling pipes are wound around each electromagnetic coil, and a cooling medium circulates in the pipes, taking away the heat generated by the coils through a heat exchange system. The cooling system comprises a circulating pump and a radiator, and can be automatically adjusted to ensure that the cooling effect is always optimal.
The in-vivo magnetic control system 30 also integrates a digital control system and a programmable control module, allows a user to adjust magnetic field parameters in real time, and presets a magnetic field change pattern according to operation requirements. The second computer 34 is responsible for the operation and management of the overall system, and the user can set target parameters (e.g., strength, direction, and gradient) of the magnetic field through the interface. The second computer 34 includes a second host 341 and a magnetic field control display 342.
The second relay 37 and the superconducting electromagnet coil 312 are electrically connected by a wire. The signal input end of the second power amplifier 36 is connected with the analog signal output end of the second data acquisition card 35, and the output end of the second power amplifier 36 is connected with the power input end of the second relay 37 through a connecting wire. The second data acquisition card 35 is connected with the second computer 34 through a USB communication interface.
The second computer 34 transmits preset signal parameters. The second data acquisition card 35 receives the digital signal from the second computer 34 and converts it into an analog signal. These analog signals represent the required magnetic field strength and frequency and are then transmitted to a second signal amplifier.
The second power amplifier 36 can power-amplify and convert the analog signal output from the second data acquisition card 35 into a current value required for driving the coil, so as to ensure that the coil generates a required magnetic field strength.
The second hall sensor is connected with the second data acquisition card 35, and the strength and the distribution condition of the magnetic field are fed back in real time. All signals are transmitted through optical fibers or high-shielding data lines so as to avoid electromagnetic interference and ensure the accuracy and stability of the system.
The OCT imaging system 33 can detect the position of the micro-scale magnetically controlled cell micro-clamp 10 in vivo in real time. A specific OCT imaging system 33 can achieve an axial resolution of 1-15 microns and a lateral resolution of 10-20 microns. The imaging depth is then dependent on the optical properties of the sample and the wavelength of the light source. For biological tissue, the imaging depth of the OCT imaging system 33 is typically in the range of 1-3 mm, and can image deep into the tissue, thereby providing detailed structural information inside the tissue. The OCT imaging system 33 includes an OCT imager host 331, an OCT imager scanning device 332, and an imaging display screen 333. Referring to fig. 10, an imaging display 333 may display the blood vessel 7 in the human body and the micro-magnetic control cell micro-clamp 10 in the blood vessel observed under OCT imaging.
The specific steps of the micro-clamp cell operation by using the in-vitro magnetic control system are as follows:
The first computer transmits digital signals via USB serial communications, and the waveform (typically expressed in mathematical formulas) of the output signals is set in the computer program and transmitted to the first data acquisition card 22 via the software API interface. A digital-to-analog converter (DAC) in the first data acquisition card 22 reads the digital signal sent by the computer as a strong and weak signal and an alternating frequency, and converts it into an analog signal. Because the analog signal itself is weak in voltage and insufficient to drive the three-dimensional helmholtz coil 21 to produce a magnetic field of the strength required to drive the micro clamp, synchronous multiple amplification of the analog signal is required using the first power amplifier 23. The amplified voltage signal is input to the three-dimensional helmholtz coil 21. Magnetic fields with different intensities, gradients, frequencies and directions are generated according to different input signals. Wherein the magnetic field strength can be generated by varying the amplitude of the signal waveform in a computer program, the magnetic field frequency can be generated by varying the signal period, and the magnetic field direction can be generated by generating different signal strength combinations through XYZ coils. In the case where the current direction and the magnitude of two coils in a set of coils are identical (the current direction is switched by a relay), the magnetic field generated in the middle of the set of coils can be regarded as a uniform magnetic field with constant field strength. In the case where the two coils in a set of coils are not identical in current direction but are identical in magnitude, a gradient magnetic field of constant gradient can be generated between the coils from the central region to the two ends of the coil set. When a uniform magnetic field is generated, the hall sensor inside the coil outputs the detected magnetic field strength in real time, and generates a signal to be input to the analog input terminal of the first data acquisition card 22. The computer program can adjust the magnetic field intensity in real time according to the signals, so as to achieve closed-loop control. The cell detection module is used for observing the sample in real time, including the micro-clamp and cells or biological tissues in the surrounding environment. The sample image is collected by the camera and transmitted back to the user interaction interface of the computer in real time through the USB interface. The experimental operator can control the micro-clamp through the computer user interaction interface, and apply different magnetic field control signals according to the pose and the form of the micro-clamp, so that the direction and the opening and closing of the micro-clamp are changed.
The micrometer-scale magnetic control cell micro clamp 10 is made of super-elastic photoresist material and Fe 3O4 magnetic particles. Since these magnetic particles have superparamagnetism, and the magnetic moments of the magnetic particles in the head-to-tail direction within the micro-scale magnetically controlled cell micro-clamp 10 are aligned along the magnetization axis, the magnetic moments thereof are aligned with the magnetic field direction in the presence of an external magnetic field. When the direction of the magnetic field changes, the magnetic moments of the magnetic particles are aligned again, and the micro-clamp is driven to synchronously change direction. After a rotating uniform magnetic field with the intensity of 5mT is applied by the external magnetic control system 20, the micro-clamp can synchronously rotate along with the magnetic field. In low reynolds number environments, the motion inertia is negligible and the motion of the particles is dominated by the viscous drag of the fluid. The viscous force interacts with the fluid flow created by the rotation of the micro-clamp, thereby creating a net displacement that causes the micro-clamp to tumble and move forward. Due to the constraint of the elastic element 2, the micro-clamp is in a closed state, i.e. an included angle is formed between the two clamp bodies 1.
When the micro-clamp reaches the target position, a rotating uniform magnetic field with the intensity of 15mT is applied through the external magnetic control system 20. At this time, since the micro-clamp is placed in a uniform magnetic field, the intensity of the magnetic field is changed, and the magnetization intensity and magnetic moment of the magnetic particles are also changed. The stronger magnetic field can magnetize the magnetic particles stronger and generate larger magnetic moment, so that larger moment is applied to drive the structure of the micro-clamp to deform. Since the micro-clamp is in a closed state before a magnetic field is applied, the magnetization axis direction of the micro-clamp deflects inwards at the clamping opening, so that the magnetization axis is aligned to the magnetic field direction to a greater extent after the magnetic moment is enhanced. The deflection of the magnetization axis generated by the deflection can lead the clamp body 1 to overcome the resistance of the elastic piece 2, the included angle between the two clamp bodies 1 is reduced to be close to zero, the micro-clamp is in an open state, after the cell 3 enters the jaw, the magnetic force born by the clamp body 1 is reduced after a rotating uniform magnetic field of 5mT is applied, the clamp body is again closed under the constraint of the elastic piece 2, and the micro-clamp is in a clamping state. The movement of the micro-clamp is realized by applying a rotating magnetic field, so that the micro-clamp moves forwards in a spiral way, and after the cell 3 is transported to a designated position, a strong magnetic field is applied, the jaw is opened, and the cell 3 is released.
In addition, when the micro-clamp is placed in a gradient magnetic field, the intensity of the magnetic field is nonuniform in space, and the magnetic moment of magnetic particles in the micro-clamp can be subjected to a magnetic force consistent with the gradient direction in the magnetic field. The stronger the field, the greater the attractive force. Under the condition of applying a gradient magnetic field, the motion path of the micro-nano robot can be accurately regulated by controlling the direction of the magnetic field. The robot moves along the new gradient direction by changing the direction of the magnetic field gradient, so that the transportation of cells can be realized by switching the uniform magnetic field and the gradient magnetic field.
In order to prevent the micro-clamp from missing the target cells when the micro-clamp rolls and approaches the target cells in actual use, a gradient magnetic field can be applied to the micro-clamp to enable the micro-clamp to move in parallel when the micro-clamp approaches the cells. Specifically, when the cells are clamped, a (15 mT) rotating uniform magnetic field with high intensity can be applied to drive the micro-clamp to roll and move to approach the target cells, and the jaws are in an open state. When the micro-clamp is close to the target cell (< 100 um), the rotating uniform magnetic field is closed, the magnetic field is switched into a gradient magnetic field with the gradient of 500mT/m, and the gradient increasing direction of the gradient magnetic field is consistent with the advancing direction of the driving micro-clamp. When the micro-clamp touches the cell, the gradient magnetic field is closed, and the jaw of the micro-clamp is closed and clamps the cell. After sandwiching the cells, the magnetic field was switched to a rotating uniform magnetic field of lesser strength (5 mT) and the cells were transported. Finally, the transfer target position is reached by controlling the change of the magnetic field direction.
In summary, the operation and movement of the micro-magnetic control cell micro-clamp 10 in the application are controlled by the magnetic field, so that stable cell transportation and triggering release can be realized. In addition, by adjusting the opening and closing deformation amplitude of the micro-clamp, the micro-clamp can be used for gently grabbing cells or other objects with different geometric shapes and sizes, such as cancer cells, sperms and the like, and simultaneously can also be used for grabbing and removing micro-coagulation foreign matters.
The method of performing micro-clamp cell manipulation using the in vivo magnetic control system is similar to the method of performing micro-clamp cell manipulation using the in vitro magnetic control system, except that all magnetic fields are applied by the in vivo magnetic control system 30, and the in vivo magnetic control system 30 is larger than the in vitro magnetic control system in terms of the magnitude of the experimental uniform magnetic field and the gradient of the gradient magnetic field in the human body, and the observed sample is imaged by OCT, not by a microscope, which will not be described in detail herein.
Example 2:
Referring to fig. 11 and 12, embodiment 2 is similar to embodiment 1 in structure except that the jaw bodies 1 are claw-shaped jaw bodies, each jaw body 1 includes four claw jaws 12, and thus, when the micro-pliers are in a clamped state, a spherical jaw formed of two perpendicular rings is formed between the two jaw bodies 1. In this way, the claw-shaped pincers can form a closed contour, and the grabber can be completely closed in the jaw to prevent the grabber from sliding out when grabbing fine objects (such as sperms).
The present application is not limited to the above embodiments, and any changes or substitutions within the technical scope of the present application should be covered by the scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.
Claims (9)
1. The micro-magnetic control cell micro-clamp system for medical detection and diagnosis is characterized by comprising a micro-magnetic control cell micro-clamp, an in-vitro magnetic control system and an in-vivo magnetic control system, wherein the in-vitro magnetic control system can generate a first external magnetic field for driving the micro-magnetic control cell micro-clamp to perform cell operation in vitro, the in-vivo magnetic control system can generate a second external magnetic field for driving the micro-magnetic control cell micro-clamp to perform cell transportation operation in vivo, the micro-magnetic control cell micro-clamp comprises two clamp bodies and an elastic piece, the two clamp bodies are oppositely arranged, the elastic piece can restrict the two clamp bodies to a clamp opening state, the clamp bodies are formed by processing super-elastic photoresist material doped with super-paramagnetic material, and the clamp bodies can be opened or closed under the action of the first external magnetic field or the second external magnetic field so as to grasp or release cells and transport the cells to a preset position.
2. The micro-scale magnetically controlled cell micro-clamp system for medical detection and diagnosis according to claim 1, wherein the clamp body is capable of clamping single cells in the jaws when in the closed state.
3. The micro-scale magnetically controlled cell micro-clamp system for medical detection and diagnosis according to claim 2, wherein the clamp body is a serrated clamp body or a claw clamp body.
4. The micro-scale magnetically controlled cell micro-clamp system for medical detection and diagnosis according to claim 3, wherein the head-tail direction of the clamp body is an easy axis of magnetization.
5. The micro-scale magnetic control cell micro-clamp system for medical detection and diagnosis according to claim 4, wherein the first external magnetic field and the second external magnetic field are both variable magnetic fields capable of being converted between a rotating uniform magnetic field and a gradient magnetic field, the rotating uniform magnetic field is a rotating uniform magnetic field with variable magnetic field intensity, when the first external magnetic field is converted into the rotating uniform magnetic field with magnetic field intensity larger than 7mT, the micro-scale magnetic control cell micro-clamp is driven to roll forward and open, when the first external magnetic field is converted into the rotating uniform magnetic field with magnetic field intensity smaller than 7mT, the micro-scale magnetic control cell micro-clamp is driven to roll forward and close, when the first external magnetic field is converted into the gradient magnetic field with gradient of 0-1T/m or when the second external magnetic field is converted into the gradient magnetic field with gradient of 0-5T/m, the micro-scale magnetic control cell micro-clamp is driven to roll forward.
6. The micro-scale magnetically controlled cell micro-clamp system for medical detection and diagnosis according to claim 5, wherein an included angle is formed between the two clamp bodies, and the magnitude of the included angle between the two clamp bodies is controlled by controlling the intensity of the first external magnetic field and the second external magnetic field to enable the easy axis of magnetization to deflect.
7. The micro-scale magnetic control cell micro-clamp system for medical detection and diagnosis according to claim 1, wherein the external magnetic control system comprises a three-dimensional Helmholtz coil, a first data acquisition card, a first power amplifier, a first relay, a first computer and a cell detection module, wherein the three-dimensional Helmholtz coil and the cell detection module are arranged on a bearing bracket, a sample platform is arranged at the center of the three-dimensional Helmholtz coil and used for placing a culture dish for culturing cells to be operated, the cell detection module is in communication connection with the first computer and can monitor living tissues and cells and monitor the position of the micro-scale magnetic control cell micro-clamp in real time, the first data acquisition card is in communication connection with the first computer, the first relay is in electric connection with the first power amplifier, and the signal input end of the first power amplifier is connected with the analog signal output end of the first data acquisition card.
8. The micrometer-scale magnetic control cell micro-clamp system for medical detection and diagnosis according to claim 7, wherein the cell detection module comprises an optical biological microscope and a microscope camera, the optical biological microscope is an inverted fluorescent microscope, an objective lens is inverted below a sample platform, and the microscope camera is connected with a trinocular port of the optical biological microscope to realize the butt joint of the microscope camera and an optical system of the optical biological microscope.
9. The micro-magnetic control cell micro-clamp system for medical detection and diagnosis according to claim 1, wherein the in-vivo magnetic control system comprises a magnetic field generator, a scanning bed, an OCT imaging system, a second computer, a second data acquisition card, a second power amplifier and a second relay, wherein the magnetic field generator comprises a body, a plurality of groups of superconducting electromagnet coils arranged on the body along the X, Y, Z axis direction, the body is of a ring-shaped or cylindrical structure capable of allowing a patient scanning bed to pass through, the OCT imaging system can detect the position of the micro-clamp of the micro-magnetic control cell in the body in real time, the second data acquisition card is in communication connection with the second computer, the second relay is in electrical connection with the superconducting electromagnet coils, the signal input end of the second power amplifier is connected with the analog signal output end of the second data acquisition card, and the output end of the second power amplifier is connected with the power input end of the second relay.
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