Microinjection device and microinjection control method

Abstract

According to the microinjection device and the microinjection control method, the problems that in microinjection membrane breaking operation, a membrane structure is high in deformation damage, solid particle injection is not facilitated, and the membrane breaking efficiency is low are solved, and the microinjection device and the microinjection control method belong to the technical field of microoperation and microinjection. The microinjection device comprises a linear motion module, a rotating module and a microneedle, the linear motion module is used for driving the microneedle to do linear motion, the rotating module is used for driving the microneedle to do rotating motion, and a driving signal of the rotating module is a periodic alternating rotating signal. A periodic alternating rotary shearing mode is adopted to replace a traditional one-way rotation or fixed vibration mode, the deformation process of the membrane is homogenized through dynamic shearing force, the deformation quantity of the membrane is reduced, the cell activity is remarkably improved, membrane penetration is accelerated through the shearing fatigue effect and the crack expansion effect generated by alternating rotation, and the cell quality is improved. And the membrane breaking efficiency is further improved compared with one-way rotation.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of micromanipulation and microinjection, and particularly relates to a microinjection device and a microinjection control method. BACKGROUND

[0002] When biological objects such as organoids, somatic cells, and germ cells are precisely operated, there are problems such as low efficiency, damage caused by penetration injection, and the like. These technical shortcomings seriously restrict the application effect and reliability of microinjection in the fields of precise biomedicine such as gene editing, embryo operation, and organoid culture. SUMMARY

[0003] In view of the problems of high deformation damage to the membrane structure, difficulty in solid particle injection, and low membrane breaking efficiency in the membrane breaking operation of microinjection in the prior art, the application provides a microinjection device and a control method.

[0004] The microinjection device of the application comprises a linear motion module, a rotating module, and a microneedle.

[0005] The linear motion module is used to drive the microneedle to move linearly.

[0006] The rotating module is used to drive the microneedle to move rotationally, and the driving signal of the rotating module is a periodic alternating rotation signal.

[0007] In one possible design, the linear motion module of the application comprises a T-axis linear motion module, and the movement direction of the T-axis linear motion module coincides with the feeding direction of the microneedle in the movement process.

[0008] In one possible design, the linear motion module of the application comprises an X-axis linear motion module, a Y-axis linear motion module, and a Z-axis linear motion module, and the movement axes of the T-axis linear motion module, the Y-axis linear motion module, and the Z-axis linear motion module all have an included angle.

[0009] In yet another possible design, the device of the application further comprises a position detection module and a compensation module.

[0010] The position detection module is used to collect the position of the needle tip of the microneedle in the movement process.

[0011] The compensation module is used to determine the eccentric trajectory of the microneedle shaft according to the position of the needle tip, and to control the linear motion module to perform eccentric compensation according to the eccentric trajectory of the microneedle shaft.

[0012] In a possible design, the compensation module is specifically configured to fit a relationship function between the compensation amount of the linear motion module and the rotation angle of the microneedle according to the shaft eccentric trajectory, and derive the compensation amount of the linear motion module corresponding to the current rotation angle of the microneedle through the relationship function to perform eccentric compensation.

[0013] In a possible design, the position detection module is a vision acquisition module, configured to capture an image of the microneedle in motion, obtain the position coordinates of the tip of the microneedle in the image, and determine the shaft eccentric trajectory of the microneedle.

[0014] In another possible design, the device further includes a force detection module and an impedance controller.

[0015] The force detection module is configured to detect the force of the microneedle in the process of penetrating the target object during injection.

[0016] The impedance controller is configured to control the linear motion module and the rotation module according to the change of the detected force.

[0017] When the force detected by the force detection module is less than a reference force, the impedance controller controls the linear motion module and the rotation module to feed the microneedle on the target object and periodically and alternately rotate and shear; when the force detected by the force detection module is greater than the reference force, the impedance controller controls the linear motion module to slow down the feeding or stop the feeding of the microneedle, and the rotation module keeps the periodic and alternating rotation and shear.

[0018] The present application also provides a microinjection control method applied to a microinjection device including a microneedle, and the control method includes:

[0019] controlling the microneedle to perform linear motion;

[0020] controlling the microneedle to perform rotational motion based on a periodic and alternating rotation signal as a driving signal.

[0021] In a possible design, the method further includes detecting the force of the microneedle in the process of penetrating the target object during injection, and controlling the motion of the microneedle according to the change of the detected force.

[0022] When the detected force is less than a reference force, the microneedle is controlled to feed on the target object and periodically and alternately rotate and shear; when the detected force is greater than the reference force, the microneedle is controlled to slow down the feeding or stop the feeding, while keeping the periodic and alternating rotation and shear.

[0023] In another possible design, the microinjection device further includes a linear motion module and a rotation module.

[0024] controlling the microneedle to perform linear motion, including:

[0025] The microneedle is driven by the linear motion module to move linearly.

[0026] The microneedle is controlled to rotate based on a periodic alternating rotation signal as a driving signal, and the method comprises the following steps:

[0027] The microneedle is driven by the rotation module to rotate, and the driving signal of the rotation module is a periodic alternating rotation signal.

[0028] The method further comprises the following steps:

[0029] The position of the tip of the microneedle in the motion process is collected.

[0030] According to the position of the tip, the eccentric trajectory of the axis of the microneedle is determined.

[0031] The linear motion module is controlled to perform eccentric compensation according to the eccentric trajectory of the axis.

[0032] In one possible design, the linear motion module is controlled to perform eccentric compensation according to the eccentric trajectory of the axis, and the method comprises the following steps:

[0033] According to the eccentric trajectory of the axis, the parameters in the relationship function between the compensation amount of the linear motion module and the rotation angle of the microneedle are fitted.

[0034] According to the current rotation angle of the microneedle, the corresponding compensation amount of the linear motion module is obtained through the relationship function to perform eccentric compensation.

[0035] In one possible design, the method for collecting the position of the tip of the microneedle in the motion process and determining the eccentric trajectory of the axis of the microneedle comprises the following steps:

[0036] An image of the microneedle in the motion process is captured, the position coordinates of the tip of the microneedle in the image are obtained, and the eccentric trajectory of the axis of the microneedle is determined.

[0037] The beneficial effects of the present application are as follows: on the one hand, the periodic alternating rotation shear mode is used to replace the traditional unidirectional rotation or fixed vibration mode, the deformation process of the film is uniformly sheared by dynamic shear force, the film deformation is reduced, and the cell activity is significantly improved; on the other hand, the shear fatigue effect and crack propagation effect generated by the alternating rotation (such as a Sin wave and a square wave) accelerate the film penetration, and the film breaking efficiency is further improved compared with the unidirectional rotation;

[0038] In addition, the visual servo system is used for needle tip position detection and axis eccentricity compensation, the eccentricity problem of the needle tip end caused by machining and installation of the rotation module is effectively controlled, and the injection efficiency is improved;

[0039] In addition, the alternating rotation injection method allows the microneedle diameter to be appropriately enlarged, reduces the capillary force, is beneficial to solid particle injection, effectively prevents the solid particles from being thrown out, and ensures the stability of the microparticle injection.

[0040] In addition, the application integrates real-time feedback force and impedance control in the process of microneedle puncture of tissue, and dynamically adjusts the rotation parameters and feeding force according to different biological sample characteristics, breaks through the adaptability limitation of traditional technology on heterogeneous samples, and realizes efficient and accurate membrane breaking injection operation under the premise of ensuring low damage. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 A five-degree-of-freedom alternating rotation shearing microinjection device is provided for the embodiments of the application.

[0042] Figure 2 An exploded view of a single-axis rotation puncture mechanism is provided for the embodiments of the application.

[0043] Figure 3 An alternating rotation shearing microinjection principle diagram is involved in the embodiments of the application.

[0044] Figure 4 A schematic diagram of a visual servo eccentricity compensation method based on periodic trajectory learning is provided for the embodiments of the application.

[0045] Figure 5 A T-axis feeding control block diagram is involved in the embodiments of the application.

[0046] Figure 6 A flowchart of a microinjection control method is provided for the embodiments of the application. DETAILED DESCRIPTION

[0047] The technical solutions in the embodiments of the application will be described clearly and completely in the embodiments of the application in combination with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the application, not all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the application.

[0048] It should be noted that the embodiments in the application and the features in the embodiments can be combined with each other without conflict.

[0049] The application will be further described in combination with the accompanying drawings and specific embodiments, but not as a limitation of the application.

[0050] The prior art faces multiple technical bottlenecks in the operation of microinjection membrane breaking, and how to realize efficient and low-damage membrane penetration injection is always a key problem. The current common membrane puncture methods mainly include the following three methods: Method 1, direct feeding puncture: the needle tip is directly pushed axially to puncture the membrane structure, which is simple, but direct puncture relies on the direct force of the rigid needle tip, which easily causes high deformation of the membrane structure or cannot penetrate the membrane, affecting the success rate of injection and cell activity, and the fine needle tip causes serious capillary phenomenon, which is not conducive to drug release. Method 2, piezoelectric high-frequency vibration puncture: high-frequency micro-vibration is applied axially while feeding to reduce membrane deformation and improve puncture success rate. Although the high-frequency vibration driven by the piezoelectric driver can reduce the deformation, it cannot adapt to the stable injection of solid particles (such as magnetic beads), and there is a risk of particles being thrown out, and the cost of the piezoelectric driver is high. Method 3, one-way rotation puncture: one-way rotation is used to improve the shear force and realize membrane penetration. Although the one-way low-frequency rotation shear can improve the membrane breaking efficiency, it has the "membrane twisting phenomenon", and the operation time is long and easy to cause membrane structure tearing damage, and has the problem of low shear efficiency, and the rotation speed is usually low (<10° / s). In addition, the existing system generally lacks real-time force feedback and dynamic adjustment capability, and it is difficult to meet the heterogeneous needs of different biological samples.

[0051] In view of this, the embodiments of the present application provide a microinjection device, which comprises a linear motion module, a rotation module and a microneedle.

[0052] The linear motion module drives the microneedle to move linearly; the rotation module drives the microneedle to move rotationally, and the driving signal of the rotation module is a periodic alternating rotation signal.

[0053] In order to improve the puncture efficiency and reduce the peak value of the puncture force, the embodiments introduce an alternating rotation shear mechanism in the process of microneedle puncture, generate high-frequency small-amplitude reciprocating rotation motion of the rotation shaft by control, simulate the "micro-drilling" effect, and thus assist the needle tip to penetrate the membrane structure, reduce the overall deformation and slip of the membrane.

[0054] In some embodiments, the linear motion module of the present embodiment comprises a T-axis linear motion module, and the movement direction of the T-axis linear motion module coincides with the feeding direction of the microneedle in the movement process.

[0055] The linear motion module of the present embodiment can also use a multi-axis motion module to assist in adjusting the feeding position and feeding direction of the microneedle on the target object; in some embodiments, as shown in Figure 1 The linear motion module comprises an X-axis linear motion module, a Y-axis linear motion module and a Z-axis linear motion module, the movement axes of the X-axis linear motion module, the Y-axis linear motion module and the Z-axis linear motion module are perpendicular to each other, the movement axis of the T-axis linear motion module has an angle with the movement axes of the Y-axis linear motion module and the Z-axis linear motion module, and the movement direction of the T-axis linear motion module coincides with the feeding direction of the microneedle on the target object. As shown in Figure 1As shown, the embodiment of the present application provides a five-degree-of-freedom alternating rotary shear microinjection device, which is composed of four linear motion modules X, Y, Z, T and one rotary module R. The linear motion module usually adopts the combination of ball screw pair and linear guide rail. The ball screw converts the rotary motion of the motor into linear motion, and the linear guide rail provides accurate guidance to ensure high precision and low friction of the motion. The rotary module is realized by a hollow servo motor, which can realize ±180° or even larger angle rotation. Through multi-axis linkage, the glass microneedle can be accurately moved to any position above the target cell or target object in three-dimensional space, and the needle tip can be made as consistent as possible with the normal direction of the cell membrane. The precision can reach micrometer level, which meets the injection needs of cells at different positions.

[0056] Reference Figure 2 An exploded view of a single-axis rotary puncture mechanism is provided for the embodiment of the present application. The structure of the rotary module and the microneedle is as shown in Figure 2 As shown, the microneedle of the present embodiment can be a glass microneedle. The rotary module is composed of a motor base, a hollow servo motor, a coupling, and a bushing. The motor base is a support structure for the motor, usually made of high-strength and high-rigidity materials such as aluminum alloy or stainless steel. It firmly fixes the hollow servo motor on the device to ensure the stability of the hollow servo motor during operation. The coupling is used to connect the output shaft (needle holder) of the hollow servo motor and the bushing, and is made of high-strength and high-rigidity materials such as aluminum alloy or stainless steel to ensure mechanical centring and direct torque transmission. The bushing is a precise guide component, usually made of high-precision metal materials, with a precise hole inside for shaft cooperation. The design of bushing plus coupling is beneficial to quick-release end effectors such as needle holders, and leaves space for end expansion.

[0057] Reference Figure 3 The alternating rotary shear microinjection principle is involved in the embodiment of the present application. The present embodiment adopts periodic alternating rotary shear for microinjection to enhance the membrane penetration efficiency, as shown in Figure 3The microneedle is driven by a set of periodic alternating rotation signals (such as sine wave or square wave) during the movement to achieve back and forth shearing motion, while feeding along the T-axis direction. When the needle tip contacts the cell membrane, organoid membrane or yolk membrane, etc. Target structure, the alternating rotation generates a periodic shear stress on the membrane surface, inducing fatigue effect and crack propagation effect of the membrane structure, thereby effectively reducing the force threshold required for puncture. For impedance control strategy, the microinjection device of the embodiment also includes a force detection module and an impedance controller, the force detection module is used to detect the force of the microneedle during the puncture of the target object during injection, and the impedance controller is used to control the movement of the linear motion module and the rotation module according to the change of the detected force. Exemplarily, the force detection module of the embodiment can be realized by using strain gauge sensor, optical sensor, etc. The Polyvinylidene Fluoride (PVDF) film pressure sensor selected by the embodiment can monitor the force change in the puncture process in real time, and dynamically adjust the feeding speed of the T-axis according to the preset force trajectory, the core principle of which involves shear force dynamic implementation and viscoelastic membrane rupture mechanism. The glass microneedle alternately rotates (clockwise / counter-clockwise alternately) at an angular velocity ω, generating a periodic shear stress τ on the membrane surface:

[0058]

[0059] wherein:

[0060] μ: shear modulus of the membrane (elastic response), η: viscosity coefficient of the membrane (damping response), γ(t): shear strain, related to the rotation angle θ(t) of the microneedle:

[0061] γ(t) = r·θ(t)

[0062] r is the radius of the microneedle, and the alternating rotation angular velocity is ω(t).

[0063] During puncture, the total puncture force F is decomposed into:

[0064] F = F 轴向 + F 剪切 The axial force is measured by the PVDF film pressure sensor, F 轴向 = k·δ, k is the stiffness of the film, and δ is the puncture depth; the shear force is contributed by the alternating rotation, F 剪切 = γ(t)·A, A is the contact area of the microneedle and the membrane, and when the shear stress exceeds the membrane rupture stress limit, the membrane breaks.

[0065] In the embodiment, when the force detected by the force detection module is less than the reference force, the impedance controller controls the linear motion module and the rotating module to drive the microneedle to feed on the target object and periodically alternate rotation shearing; when the force detected by the force detection module is greater than the reference force, the impedance controller controls the linear motion module to slow down or stop the microneedle feeding, and the rotating module keeps the periodic alternating rotation shearing, that is, the rotating module normally works, and only the rotating module controls the alternating rotation shearing action of the microneedle, so as to avoid damage to the target object, thereby realizing compliant contact, force peak limitation and self-adaptive adjustment in the puncture process, and significantly improving the safety and success rate of puncture. The control block diagram is shown in Figure 4 .

[0066] In some embodiments, due to the machining error of the rotating shaft, the microneedle may generate an eccentric trajectory when rotating, which affects the puncture accuracy. In order to overcome the eccentric problem, a servo compensation mechanism is introduced to monitor and dynamically correct in real time through multi-axis linkage, so as to ensure the high accuracy and high stability of the puncture process. Specifically, the microinjection device of the present application can further include a position detection module and a compensation module, wherein:

[0067] The position detection module collects the position of the needle tip of the microneedle in the movement process;

[0068] The compensation module determines the shaft eccentric trajectory of the microneedle according to the position of the needle tip, and controls the linear motion module to compensate for the eccentricity according to the shaft eccentric trajectory.

[0069] In the embodiment, the compensation can be performed by the microneedle movement before entering the target object, and the coarse compensation is performed according to the shaft eccentric trajectory, and the fine compensation is performed after entering the target object; or the compensation can be performed only after entering the target object, and the shaft eccentric trajectory collected at the moment of entering the target object is also sufficient for compensation amount calculation.

[0070] In some embodiments, the compensation module fits the parameters of the relationship function between the compensation amount of the linear motion module and the rotation angle of the microneedle according to the shaft eccentric trajectory, and obtains the corresponding compensation amount of the linear motion module through the relationship function according to the current rotation angle of the microneedle to compensate for the eccentricity. For example, some non-contact sensors can be used to collect the position of the needle tip of the microneedle in the movement, and the position detection module of the embodiment can be a visual acquisition module, for example, a microscopic camera device can be used to shoot images of the microneedle in the movement, obtain the position coordinates of the needle tip of the microneedle in the image, and determine the shaft eccentric trajectory of the microneedle. The compensation module of the embodiment adopts a visual servo eccentric compensation method based on periodic trajectory learning, and the compensation process is as follows, see Figure 4 .

[0071] Prepare for image acquisition. Use a microscopic camera to capture a real-time image of the microneedle tip and extract its position coordinates in the image. Convert this coordinates to actual coordinates and store the current sampling point (x, y) in a trajectory cache. The trajectory cache uses a sliding window structure, retaining the data of the most recent M cycles. N points are sampled per cycle, and the total number of cached points is M × N.

[0072] Specifically, the image of the needle tip in motion can be collected before the needle penetrates the target object, when the microneedle is idling, and the parameters can be preliminarily fitted. The parameters can also be updated during the microneedle penetration process.

[0073] Store the current needle tip position and the corresponding rotation angle in the trajectory buffer (sliding window), and retain the data of the most recent multiple cycles;

[0074] This embodiment uses the sine-cosine model to describe the relationship between the linear motion module compensation amount and the microneedle rotation angle function: ΔZ(θ)=ΔY(θ)tanβ, using the least squares fitting parameters: A x 、A y 、

[0075] A x 、A y represents the corresponding amplitude, is the corresponding phase, β is the angle between the rotation axis and the horizontal plane; ΔX(θ), ΔY(θ), ΔZ(θ) are the compensation amounts of the X-axis linear motion module, Y-axis linear motion module, and Z-axis linear motion module; the parameters in the ΔX(θ) and ΔY(θ) functions are fitted using the data of the most recent multiple cycles, and the exponential sliding average is used to update the parameters, P upload =α·P new +(1-α)·P old , where P new is the newly obtained fitting parameter, P upload is the parameter after exponential sliding average, α is the weight factor;

[0076] In real-time operation, according to the current rotation angle θ, the fitting function is called to calculate ΔX(θ) and ΔY(θ) and perform compensation.

[0077] By real-time identification of the needle tip trajectory and dynamic correction, eccentricity compensation is achieved.

[0078] This embodiment also provides a microinjection control method, which is applied to the above-mentioned microinjection device, such as Figure 6 As shown, the control method includes:

[0079] The microneedle target object is controlled to move linearly; the microneedle is controlled to move in rotation based on the periodic alternating rotation signal as a driving signal.

[0080] The present embodiment adopts a periodic alternating rotational shear mode instead of the traditional unidirectional rotation or fixed vibration mode. The deformation of the film is reduced by homogenizing the deformation process of the film through dynamic shear force, which significantly improves the cell activity. The shear fatigue effect and crack propagation effect generated by the periodic alternating rotation (such as sine wave or square wave) accelerate the film penetration, thereby effectively reducing the force threshold required for puncture and further improving the film breaking efficiency compared to unidirectional rotation. In microinjection and other micro-operation tasks, the target structure (such as cell membrane, organoid epidermis, etc.) usually has high softness and high fragility, and is extremely sensitive to changes in puncture force. The traditional position control method is prone to the following problems during puncture: the puncture force is too large, causing the membrane structure to tear or deform excessively; the contact instant impact is large, affecting the puncture stability; and lacking physical feedback regulation ability for the "membrane contact-penetration" process. In order to avoid damage to the target object, in some embodiments, impedance control strategy can be introduced to change the puncture process from "position dominant" to "force dominant", and force feedback is reflected in the feed direction;

[0081] During the puncture process, the user first sets the desired puncture force trajectory or maximum force threshold, and initializes the impedance model parameters (equivalent mass M, damping B, stiffness K). The impedance control model is:

[0082]

[0083] When the microneedle moves and contacts the membrane structure of the target object, the contact force of the needle tip is collected in real time and compared with the set desired force;

[0084] According to the error, the feed speed of the microneedle is dynamically adjusted to make the output meet the desired "force-displacement" relationship. Specifically, the force during the puncture of the target object by the microneedle is detected; and the motion of the microneedle is controlled according to the detected force:

[0085] When the detected force is less than the reference force, the microneedle is controlled to feed on the target object and periodically alternatingly rotate and shear;

[0086] When the detected force is greater than the reference force, the microneedle is controlled to slow down or stop feeding, while maintaining periodic alternating rotation and shear to assist in breaking the membrane.

[0087] The impedance control strategy of the present embodiment can realize compliant contact, force peak limitation and adaptive adjustment during puncture, significantly improving the safety and success rate of puncture.

[0088] Based on the above microinjection device, a linear motion module and a rotation module are further included. In some embodiments, the method for controlling the linear motion of the microneedle includes:

[0089] The linear motion module drives the microneedle to move linearly;

[0090] In some embodiments, the present embodiment is based on a method for controlling the rotational movement of microneedles by using a periodic alternating rotation signal as a driving signal, which comprises:

[0091] The rotation module drives the microneedles to rotate, and the driving signal of the rotation module is a periodic alternating rotation signal.

[0092] In some embodiments, the present embodiment is based on a method for controlling the rotational movement of microneedles by using a periodic alternating rotation signal as a driving signal, which comprises:

[0093] Collecting the position of the needle tip of the microneedle during the movement;

[0094] According to the position of the needle tip, the eccentric trajectory of the axis of the microneedle is determined.

[0095] According to the eccentric trajectory of the axis, the eccentricity compensation of the linear motion module is controlled.

[0096] In some embodiments, the present embodiment is based on a method for controlling the rotational movement of microneedles by using a periodic alternating rotation signal as a driving signal, which comprises:

[0097] According to the eccentric trajectory of the axis, the eccentricity compensation of the linear motion module is controlled.

[0098] According to the current rotation angle of the microneedle, the corresponding compensation amount of the linear motion module is obtained by the relationship function to perform eccentricity compensation.

[0099] For the above control method, the present embodiment provides a corresponding injection process of the microinjection device and the microinjection control method based on the present embodiment in actual application as follows:

[0100] 1. Injection object and device configuration

[0101] Injection target: spherical organoids with a diameter of about 300 μm; injection needle type: self-made glass microneedle with an outer diameter of about 30 μm at the tip;

[0102] Injection method: using the five-degree-of-freedom alternating rotation shear injection system of the present application;

[0103] Injection needle holder: driven by a hydraulic micropump to control the injection amount;

[0104] Injection liquid content: containing magnetic microbeads with a diameter of about 20 μm;

[0105] Observation system: high-resolution microscopic imaging system (> 60 fps) for real-time tracking of the contact state of the needle tip and the organoid;

[0106] 2. Control parameter setting:

[0107] Reference force trajectory is a constant value F d= 300 μN, the force threshold is 350 μN, and the feeding stops when the threshold is exceeded;

[0108] The shaft rotation speed of the rotation module is ω = 0.1 sin (20πt) rad / s;

[0109] The control parameters of the position detection module and the compensation module are set;

[0110] The shaft of the microneedle is at an angle of 45° with the horizontal plane;

[0111] The length of the sliding window for sampling in the compensation process is 2 rotation periods, and 10 points are sampled in each rotation period;

[0112] The compensation method is based on the sine and cosine fitting of the microneedle tip image trajectory;

[0113] The compensation axis is the joint compensation of the X-axis linear motion module, the Y-axis linear motion module, and the Z-axis linear motion module;

[0114] 3. Injection process:

[0115] (1) Fix the organoid in the integrated PVDF membrane micropore array;

[0116] (2) The needle tip approaches the surface of the organoid;

[0117] (3) Real-time identification of the needle tip position and spatial point compensation;

[0118] (4) Start the linear motion module and the rotation module to drive the microneedle feeding and alternating rotation shear;

[0119] (5) The force detection module monitors the force during the needle penetration of the target object in real time;

[0120] (6) When the force approaches 300 μN, the system enters a compliant contact state: alternating rotation shear and axial feeding are normally carried out, and adaptive control is performed;

[0121] (7) If the force exceeds the threshold, pause the feeding of the linear motion module, and only keep the alternating rotation shear of the rotation module to break the membrane;

[0122] (8) After successful membrane penetration, the liquid pump drives the syringe to complete micro-injection;

[0123] (9) After the injection is completed, the needle is automatically withdrawn, and the system is reset.

[0124] 4. Experimental indicators

[0125] (1) Puncture success rate: > 90%;

[0126] (2) Maximum puncture force: controlled within 350 μN;

[0127] (3) The organoid structure remains intact without obvious rupture or deformation;

[0128] (4) The injection solution is uniformly released, and the magnetic beads are visible in the target object.

[0129] The present application realizes high-precision and low-damage injection operation in soft micro target objects such as organoids by introducing a micro-force adjustment mechanism based on impedance control and a small-amplitude alternating rotary shear strategy. This technical means can significantly reduce the risk of target object rupture while ensuring the success rate of puncture, and improve the stability and flexibility of injection, especially suitable for force-controlled fine operation on small biological structures, with good biocompatibility and repeatability, significantly better than the traditional rigid needle insertion method.

[0130] Although the present application is described herein with reference to particular embodiments, it should be understood that these examples are merely illustrative of the principles and applications of the present application. It should therefore be understood that numerous modifications can be made to the illustrative embodiments, and that other arrangements can be devised without departing from the spirit and scope of the present application as defined by the appended claims. It should be understood that different dependent claims and features herein can be combined in ways other than the original claims describe. It can also be understood that features described in connection with separate embodiments can be used in other embodiments.

Claims

1. A microinjection device, characterized in that Includes linear motion module, rotation module and microneedle; The linear motion module is used to drive the microneedle to perform linear motion; The rotation module is used to drive the microneedle to rotate, and the driving signal of the rotation module is a periodic alternating rotation signal.

2. The microinjection device according to claim 1, characterized in that The linear motion module includes a T-axis linear motion module, and the motion direction of the T-axis linear motion module coincides with the feeding direction of the microneedle during the motion process.

3. The microinjection device according to claim 2, characterized in that The device also includes a position detection module and a compensation module; The position detection module is used to collect the position of the tip of the microneedle during the movement; The compensation module is used to determine the axis eccentric trajectory of the microneedle according to the position of the needle tip, and control the linear motion module to perform eccentricity compensation according to the axis eccentric trajectory.

4. The microinjection device according to claim 3, characterized in that The compensation module is specifically used to fit the parameters of the relationship function between the compensation amount of the linear motion module and the rotation angle of the microneedle according to the axis eccentricity trajectory, and to obtain the corresponding compensation amount of the linear motion module through the relationship function according to the current rotation angle of the microneedle to perform eccentricity compensation.

5. The microinjection device according to claim 3, characterized in that The position detection module is a visual acquisition module, which is used to capture the image of the microneedle in motion, obtain the position coordinates of the needle tip of the microneedle in the image, and determine the eccentric trajectory of the microneedle axis.

6. The microinjection device according to claim 1, characterized in that The device also includes a force detection module and an impedance controller; The force detection module is used to detect the force of the microneedle when puncturing the target object during injection; The impedance controller is used to control the movement of the linear motion module and the rotation module according to the change of the detected force: Among them, when the force detected by the force detection module is less than the reference force, the impedance controller controls the linear motion module and the rotation module to drive the microneedle to feed on the target object and perform periodic alternating rotation and shear; when the force detected by the force detection module is greater than the reference force, the impedance controller controls the linear motion module to slow down or stop the feeding of the microneedle, and the rotation module maintains periodic alternating rotation and shear.

7. A microinjection control method, characterized in that: Applied to a microinjection device, the microinjection device includes a microneedle, and the control method includes: controlling the microneedle to move linearly; The microneedle is controlled to perform rotational motion based on a periodic alternating rotation signal as a driving signal.

8. The microinjection control method according to claim 7, characterized in that: The method further comprises: detecting the force of the microneedle when piercing a target object during injection; The microneedle movement is controlled according to the detected force change: When the detected force is less than the reference force, the microneedle is controlled to feed on the target object and perform periodic alternating rotation shearing; when the detected force is greater than the reference force, the microneedle is controlled to slow down or stop feeding while maintaining periodic alternating rotation shearing.

9. The microinjection control method according to claim 7, characterized in that: The microinjection device also includes a linear motion module and a rotation module; The controlling the microneedle to move linearly comprises: The microneedle is driven to perform linear motion by the linear motion module; The method of controlling the microneedle to rotate based on the periodic alternating rotation signal as a driving signal includes: The microneedle is driven to rotate by the rotation module, and the driving signal of the rotation module is a periodic alternating rotation signal; The method further comprises: collecting the position of the tip of the microneedle during the movement; determining an eccentric trajectory of the microneedle axis according to the position of the needle tip; The linear motion module is controlled to perform eccentricity compensation according to the axis eccentricity trajectory.

10. The microinjection control method according to claim 9, characterized in that: The controlling the linear motion module to perform eccentricity compensation according to the axis eccentricity trajectory includes: Fitting parameters in a relationship function between the compensation amount of the linear motion module and the rotation angle of the microneedle according to the axis eccentricity trajectory; According to the current rotation angle of the microneedle, the compensation amount corresponding to the linear motion module is obtained through the relationship function to perform eccentricity compensation.

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