Intelligent micro-flow magnetic control biological mixed sperm robot precise targeted drug delivery method

Abstract

The invention discloses an intelligent micro-flow magnetic control biological mixed sperm robot precise targeted drug delivery method, and belongs to the technical field of biomedical engineering and micro-nano robots. The method comprises the following steps: preparing a magnetic microfluidic carrier robot with a three-dimensional multi-spiral Tesla valve structure through 3D micro-nano printing; the sperm cells and the medicine are combined through electrostatic self-assembly to form a biological mixed cluster, and the biological mixed cluster is filled into the carrier; after the micro-robot is guided into a target biological cavity, the micro-robot is driven by an external rotating magnetic field to move directionally, and medicine leakage is prevented based on unidirectivity of a Tesla valve; a medical imaging system is used for real-time positioning and tracking and guiding to a focus area, and then a magnetic field is reversed to realize quick drug release. The method is combined with artificial intelligence to achieve automatic navigation, the problem that driving performance, visibility and biocompatibility of a micro-nano robot are difficult to consider is solved, and the method has the advantages of being large in drug loading capacity, high in targeting performance, good in biocompatibility and the like and is suitable for precise treatment of gynecological diseases.

Description

Technical Field

[0001] This invention belongs to the fields of medical materials, biomedical engineering, magnetically controlled microfluidics, micro-nano robots and precision medicine, and relates to a precise targeted drug delivery method for an intelligent microfluidic magnetically controlled bio-hybrid sperm robot. Background Technology

[0002] In the treatment of major gynecological diseases worldwide, such as ovarian cancer and cervical cancer, traditional systemic drug delivery methods suffer from poor targeting, significant side effects, and limited efficacy. While local drug delivery can alleviate these problems to some extent, it still struggles to achieve precise drug delivery deep within the lesion. Micro-nano robotics technology offers a new approach to solving this challenge, promising to achieve active targeted drug delivery in hard-to-reach cavities within the body.

[0003] However, existing micro- and nano-robots, especially those used for drug delivery, face a critical "impossible triangle" challenge: simultaneously achieving strong actuation capabilities, good medical imaging visibility, and excellent biocompatibility. For example, achieving strong actuation and clear imaging often requires loading large amounts of magnetic materials or contrast agents, but this increases the risk of toxicity and affects the robot's biological functions; conversely, prioritizing biocompatibility significantly reduces actuation performance and imaging contrast. Furthermore, achieving real-time, precise navigation and control of microrobots in complex biological environments without direct visualization is a major bottleneck hindering their clinical translation. In addition, the mobility of micro- and nano-drug delivery structures is limited in complex physiological environments; drug delivery in micro- and nano-robots often relies on surface attachments and small-scale micro- and nano-attached drug capsules on the top, resulting in limited drug capacity and difficulty in covering the entire lesion; drug delivery efficiency struggles to overcome specific physiological barriers such as the high pressure inside tumors. Current micro-nano robotics technology requires the use of biological triggering, chemical triggering, or high-temperature physical fields to separate the drug from the micro-nano robot during the drug release stage, thus completing the drug release. However, the impact of these biological, chemical, or high-temperature release mechanisms on the fragile tumor environment is not yet clear, and they have certain risks and high internal environmental disturbances. Now, we continue to use a purely mechanical, low-disturbance drug release mechanism to reduce disturbances in the lesion area.

[0004] Therefore, there is an urgent need in this field for a microrobot system and method that can effectively balance actuation, visibility, and biocompatibility, and achieve precise navigation and drug delivery in clinically relevant environments. However, current research still faces many challenges, including the trade-off between biocompatibility and safety, in vivo localization and real-time imaging, navigation limitations in blood flow and complex physiological flow fields, mass production, repeatability and scale-up, immune clearance, and short in vivo retention time. Its widespread application requires more basic research in engineering applications to adapt to various complex usage environments. To solve these problems, it is essential to invent a precise targeted drug delivery method using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot. Summary of the Invention

[0005] Purpose of the invention: The purpose of this invention is to provide a precise targeted drug delivery method for an intelligent microfluidic magnetically controlled bio-hybrid sperm robot that can effectively solve the trade-off between the actuation, visibility and biocompatibility of microrobots, train an artificial intelligence image recognition algorithm, automatically identify the cluster position, and adjust the magnetic field in real time for fully automatic navigation.

[0006] Technical solution: The present invention provides a method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot, comprising the following steps: (1) Fabrication of a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot: Magnetic nanoparticles are incorporated into the substrate through 3D micro-nano printing process to fabricate a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot. Alternatively, a non-magnetic three-dimensional multi-helix Tesla valve polymer skeleton can be printed using 3D micro-nano printing technology, and then a magnetic metal film can be deposited on the surface through physical vapor deposition or sputtering to achieve magnetism, thereby obtaining a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot. (2) Preparation of bio-hybrid clusters: Bio-hybrid clusters composed of sperm cells and targeted drugs are prepared by electrostatic self-assembly; (3) Sperm bio-hybrid magnetically controlled micro-nano robot: A bio-hybrid cluster composed of sperm cells and targeted drugs is injected into a three-dimensional multi-helical Tesla valve magnetic microfluidic carrier robot; or the three-dimensional multi-helical Tesla valve magnetic microfluidic carrier robot structure is immersed in the bio-hybrid cluster, and the bio-hybrid cluster is filled inside the magnetic microfluidic carrier robot by micro-oscillation and magnetic field control, thereby obtaining a sperm bio-hybrid magnetically controlled micro-nano robot; (4) Microfluidic magnetically controlled bio-hybrid sperm robot introduction cluster: The prepared sperm bio-hybrid magnetically controlled micro-nano robots are introduced into the lesion area within the target biological cavity or anatomical model; (5) Magnetic drive and drug delivery: An external magnetic drive system is used to generate a rotating magnetic field to wirelessly drive the sperm bio-hybrid magnetically controlled micro-nano robot, causing it to spin along a specific coordinate axis; at the same time, a medical imaging system is used to locate and track the sperm bio-hybrid magnetically controlled micro-nano robot in real time; finally, the sperm bio-hybrid magnetically controlled micro-nano robot is guided to roll within the target cavity or anatomical model, and then guided to the lesion area to release drug-loaded sperm bio-hybrid clusters, thus achieving precise drug delivery; (6) Closed-loop automatic control: Train an image recognition artificial intelligence algorithm model to automatically identify the cluster location and adjust the magnetic field in real time for fully automatic navigation, reducing dependence on operators and radiation exposure.

[0007] Furthermore, the magnetic nanoparticles mentioned in step (1) are superparamagnetic iron oxide nanoparticles (SPIONs) with a particle size of 10-45 nm and a saturation magnetization of 10-30 emu / g.

[0008] Further, the magnetic metal film in step (1) is nickel or titanium or a mixture thereof, or other metal and non-metal magnetizable materials.

[0009] Further, the magnetic structure of the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot obtained in step (1) is: a single-arm or multi-arm helical Tesla valve formed by spiral rotation along the central axis with a DNA-like structure. Among them, the multi-arm spiral Tesla valve can be combined at the top and bottom to form a single channel, or combined at one end to form a single-channel form or a multi-channel form.

[0010] Furthermore, the sperm cells mentioned in step (2) are human sperm cells or treated allogeneic sperm cells; In this process, before preparing the bio-hybrid microrobot cluster, the sperm cells are washed to remove seminal plasma and cryoprotectant. The targeted drugs include small molecule inhibitors (all known small molecule inhibitors) and large molecule drugs (all known large molecule drugs).

[0011] Furthermore, the target biological cavity in step (4) is the female reproductive tract, and the lesion area includes specific parts of the uterus, fallopian tubes or ovaries.

[0012] The external magnetic drive system described in step (5) includes a permanent magnet controlled by a robotic arm that performs rotational and translational motions. By controlling the rotation and translation of the permanent magnet, the required time-varying magnetic field is generated to drive the cluster motion. The frequency of the rotating magnetic field is 1-20 Hz, and the magnetic field strength is 5-20 mT; The medical imaging system is an X-ray fluorescence fluoroscopy imaging system or an ultrasound imaging system; The X-ray fluorescence imaging system works in conjunction with the external magnetic drive system to achieve closed-loop control and navigation based on real-time image feedback.

[0013] On the other hand, the present invention also discloses a system for implementing the above method, including an intelligent microfluidic magnetically controlled bio-hybrid sperm robot preparation module, a magnetic drive module, a medical imaging module, and a control module.

[0014] Furthermore, the intelligent microfluidic magnetically controlled bio-hybrid sperm robot preparation module is used to prepare intelligent microfluidic magnetically controlled bio-hybrid sperm robots through 3D micro-nano printing technology, or micro-nano printing with added physical vapor deposition or sputtering magnetic coating technology; it includes the preparation of magnetic induction base materials by 3D micro-nano printing technology, the fabrication of three-dimensional multi-helix Tesla valve magnetic microfluidic controlled carrier robot, and the post-processing of three-dimensional multi-helix Tesla valve magnetic microfluidic controlled carrier robot; The magnetic drive module is used to generate a rotating magnetic field that drives the movement of the cluster, and includes a permanent magnet and a drive device; wherein the permanent magnet is a robotic arm with multiple degrees of freedom. The medical imaging module is used for real-time imaging and positioning of the cluster, and it is a C-arm X-ray angiography system. The control module automatically identifies the cluster location based on feedback information received from the medical imaging module, combined with image recognition algorithms using machine learning and artificial intelligence. It then adjusts the magnetic field and robotic arm control in real time to perform fully automatic navigation and closed-loop automatic control, reducing reliance on operators and radiation exposure.

[0015] Beneficial Effects: Compared with existing technologies, this invention has the following significant advantages: 1. Breaking the "impossible triangle": Utilizing sperm cells as a natural, biocompatible drug carrier and structural template, and by loading an appropriate amount of magnetic nanoparticles, it cleverly balances driving force (magnetic response), visibility (X-ray imaging), and biocompatibility (human sperm as a natural carrier); 2. Ingeniously utilizing the Tesla valve principle, it designs a magnetically controlled three-dimensional torsional multi-arm Tesla valve microfluidic one-way valve micro-nano robot. Compared with all current micro-nano drug delivery robots, it only needs to reverse the rotation direction of the permanent magnet to quickly and accurately release drugs without changing the lesion site for high-temperature drug triggering. It is a purely mechanical, clean, and efficient non-biological and non-chemical triggering drug release mechanism, and it does not require magnetic field frequency... 1. **Magnetic field heating triggering or ultrasonic fragmentation triggering:** This significantly reduces disturbance to cancerous lesion areas. 2. **Real-time image navigation:** For the first time, synchronous driving and real-time imaging under a standard clinical X-ray fluorescence fluoroscopy system are achieved, providing "eyes" for precise operation in complex, non-direct-view environments. 3. **Active targeting and high drug loading:** The cluster form significantly increases drug loading and utilizes magnetic drive to achieve active targeting, overcoming the poor targeting shortcomings of traditional drug delivery methods. 4. **High controllability:** By programming and controlling the external magnetic field, the movement direction, speed, and path of the cluster can be precisely controlled. 5. **Broad application prospects:** Particularly suitable for the precise treatment of diseases within cavities such as the female reproductive tract, including cancer and endometriosis. It also provides new ideas for targeted drug delivery to other cavities, such as the digestive tract and blood vessels. Attached Figure Description

[0016] Figure 1This is an overview diagram of the autonomous control strategy of the intelligent microfluidic magnetically controlled bio-hybrid sperm robot precise targeted drug delivery method and system in this invention; Figure 2 This is a schematic diagram of the autonomous navigation of the intelligent microfluidic magnetically controlled bio-hybrid sperm robot precise targeted drug delivery method and system in this invention; Figure 3 This is a schematic diagram of the intelligent microfluidic magnetically controlled bio-hybrid sperm robot performing X-ray guided magnetic navigation in a female reproductive tract model according to Embodiment 1 of the present invention; wherein, Figure (a) is a schematic diagram of its location in the uterine cavity; Figure (b) is a schematic diagram of its entry into the right fallopian tube; Figure 4 These are scanning electron microscope (SEM) images of the drug-loaded cluster in the sperm bio-hybrid microrobot of the present invention, showing drug nanoparticles encapsulated on the surface of sperm cells; wherein, Figure (a) is a schematic diagram of the structure of the sperm bio-hybrid microrobot; Figure (b) is a scanning electron microscope image of the sperm bio-hybrid microrobot; Figure 5 This is a front elevation view of the dual-cantilever three-dimensional Tesla valve magnetic microfluidic carrier robot in an embodiment of the present invention; Figure 6 This is a perspective view of the dual-cantilever three-dimensional Tesla valve magnetic microfluidic carrier robot in an embodiment of the present invention; Figure 7 This is a side view of the dual-cantilever three-dimensional Tesla valve magnetic microfluidic carrier machine in an embodiment of the present invention; Figure 8 This is a front elevation view of the three-cantilever three-dimensional Tesla valve magnetic microfluidic carrier robot in an embodiment of the present invention; Figure 9 This is a perspective view of the three-cantilever three-dimensional Tesla valve magnetic microfluidic carrier robot in an embodiment of the present invention; Figure 10 This is a side view of the three-cantilever three-dimensional Tesla valve magnetic microfluidic carrier robot in an embodiment of the present invention; Figure 11 This is a schematic diagram of a single cantilever of the Tesla valve before torsional deformation in an embodiment of the present invention; In the figure: 1 is a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot, 2 is a sperm cell, 3 is a female or transgender human uterine contour profile model, 4 is a permanent magnet, 5 is a robotic arm, 6 is a C-arm X-ray angiography system, 7 is a female reproductive tract model, 8 is the uterus, 9 is the fallopian tube, 10 is X-ray imaging monitoring, and 11 is a targeted drug. Detailed Implementation

[0017] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0018] like Figure 1As shown, the intelligent microfluidic magnetically controlled bio-hybrid sperm robot precise targeted drug delivery method of the present invention mainly includes the following three core steps: preparation of a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1, preparation of a bio-hybrid cluster, preparation of a sperm bio-hybrid magnetically controlled micro / nano robot, introduction of the microfluidic robot (female or transgender human uterine contour profile model 3) and magnetic drive and image-guided drug delivery; specifically, it includes the following steps: Step (1) Fabrication of a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1: Magnetic nanoparticles are incorporated into the substrate through 3D micro-nano printing process to fabricate a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1. Alternatively, a non-magnetic three-dimensional multi-helix Tesla valve polymer skeleton can be printed first using 3D micro-nano printing technology, and then a magnetic metal film can be deposited on the surface through physical vapor deposition or sputtering to achieve magnetism, thereby obtaining a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1. The magnetic nanoparticles are superparamagnetic iron oxide nanoparticles with a particle size of 10-45 nm and a saturation magnetization of 10-30 emu / g. The magnetic metal film is nickel or titanium or a mixture thereof, or other metal and non-metal magnetizable materials; The structure of the obtained three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 is: a single-arm or multi-arm helical Tesla valve formed by spiraling a DNA-like structure along the central axis. The multi-arm spiral Tesla valve can be combined at the top and bottom to form a single channel, or combined at one end to form a single-channel form and a multi-channel form. Step (2), Preparation of bio-hybrid cluster: A bio-hybrid cluster consisting of sperm cells 2 and targeted drug 11 was prepared by electrostatic self-assembly; The sperm cells 2 are human sperm cells or treated allogeneic sperm cells. Before preparing the bio-hybrid microrobot cluster, the sperm cells 2 are washed in advance to remove seminal plasma and cryoprotectant. The targeted drugs include small molecule inhibitors and large molecule drugs; Step (3), Sperm bio-hybrid magnetically controlled micro-nano robot: The constructed bio-hybrid cluster is injected into the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1; or the structure of the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 is immersed in the bio-hybrid cluster, and the bio-hybrid cluster is filled inside the magnetic microfluidic carrier robot by micro-oscillation and magnetic field control to obtain the sperm bio-hybrid magnetically controlled micro-nano robot. Step (4), Microfluidic magnetically controlled bio-hybrid sperm robot cluster: The prepared sperm bio-hybrid magnetically controlled micro-nano robot is introduced into the lesion area within the target biological cavity or anatomical model; The target biological cavity is the female reproductive tract, and the lesion area includes a specific part of the uterus 8, fallopian tube 9, or ovary; Step (5), Magnetic Drive and Drug Delivery: An external magnetic drive system generates a rotating magnetic field to wirelessly drive the magnetic microfluidic carrier robot, causing it to spin along a specific coordinate axis. Due to the helical characteristics of the micro-nano robot, it generates directional thrust, thereby achieving directional movement within the body. During this process, the unidirectionality of the Tesla valve is used to prevent the drug-loaded sperm bio-mixed cluster from flowing out. At the same time, the cluster is located and tracked in real time using a medical imaging system. Finally, the magnetic microfluidic carrier robot is guided to generate rolling motion within the target cavity or model and guided to the lesion area. The external rotating field is reversed to cause the carrier robot to reverse. The unidirectionality of the Tesla valve is used again to enable the drug-loaded sperm bio-mixed cluster to release rapidly, achieving precise drug delivery. The external magnetic drive system includes a permanent magnet 4 controlled by a robotic arm 5, which is capable of rotation and translation. The frequency of the rotating magnetic field is 1-20 Hz and the magnetic field strength is 5-20 mT. Real-time imaging and positioning of an intelligent microfluidic magnetically controlled bio-hybrid sperm robot is performed using a medical imaging system, which is either an X-ray fluorescence imaging system or an ultrasound imaging system. The X-ray fluorescence imaging system works in conjunction with the external magnetic drive system to achieve closed-loop control and navigation based on real-time image feedback; After the intelligent microfluidic magnetically controlled bio-hybrid sperm robot moves to the target area, its release mechanism does not require changing the temperature or chemical environment within the target biological cavity or anatomical model. It only needs to reverse the rotation direction of the permanent magnet 4, which is a simple and efficient non-biological and non-chemical triggering method. It does not require magnetic field heating triggering through magnetic field frequency changes or ultrasonic fragmentation triggering. Step (6) Closed-loop automatic control: Train the image recognition artificial intelligence algorithm model to automatically identify the cluster location and adjust the magnetic field in real time for fully automatic navigation, reducing dependence on operators and radiation exposure.

[0019] The entire process is completed collaboratively by an integrated system, which includes an intelligent microfluidic magnetically controlled bio-hybrid sperm robot preparation module, a magnetic drive module (permanent magnet 4, robotic arm 5), a medical imaging module (C-arm X-ray angiography system 6), and a control module (not shown); among which, The T1 intelligent microfluidic magnetically controlled bio-hybrid sperm robot preparation module is used to prepare intelligent microfluidic magnetically controlled bio-hybrid sperm robots through 3D micro-nano printing technology, or micro-nano printing with added physical vapor deposition or sputtering magnetic coating technology. The T2 magnetic drive module is used to generate a rotating magnetic field that drives the movement of the cluster. The T3 medical imaging module is used for real-time imaging and localization of the cluster; The T4 control module receives feedback information from the medical imaging module and controls the movement of the magnetic drive module to achieve closed-loop control of the cluster movement.

[0020] The magnetic drive module includes a permanent magnet 4 and a robotic arm 5 that drives the permanent magnet 4 to perform multi-degree-of-freedom motion; combined with machine learning and artificial intelligence image recognition algorithms, it automatically identifies the cluster position and adjusts the magnetic field in real time for fully automatic navigation and closed-loop automatic control, reducing dependence on operators and radiation exposure; the medical imaging module is a C-arm X-ray angiography system.

[0021] Example 1: Targeted drug delivery into the female reproductive tract This embodiment demonstrates the process of targeted drug delivery to the female fallopian tube. Step 1: Preparation of Bio-Hybrid Microrobot Clusters (1) Preparation of magnetic microfluidic robot: The nano-magnetic particles of iron oxide nanoparticles are mixed into the highly compatible ink for printing. The 3D micro-nano printing process is used, and an external magnetic field is applied at the nozzle outlet. When the ink is extruded and solidified, the internal iron oxide magnetic particles will be oriented according to the direction of the magnetic field to make a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1. (2) Material preparation: Take 2 frozen male sperm cells, place them at room temperature (usually at least 22°C / 72ºF) for about 15-20 minutes, and then transfer them to a 37°C water bath to thaw. After thawing, wash the sperm cells three times with Duchenne modified Eagle medium (DMEM) by centrifugation (300 g, 5 minutes) to completely remove seminal plasma and cryoprotectant. Adjust the sperm concentration to 2.5×10^7 cells / mL using a hemocytometer. At the same time, prepare an aqueous dispersion of nanoparticles with a targeted therapeutic drug concentration of 2.8 mg / mL. (3) Electrostatic self-assembly: Take 350 μL of washed sperm suspension into a centrifuge tube; add 150 μL of targeted therapeutic drug nanoparticle dispersion with a concentration of 2.8 mg / mL (final concentration of about 1 mg / mL), and gently mix with a pipette; place the mixture on a microtube rotator and incubate overnight at room temperature to allow the targeted therapeutic drug nanoparticles to self-assemble onto the surface of sperm cell 2 through electrostatic interaction; (4) Formation of sperm bio-hybrid magnetic micro-nano robot: The structure of the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 is immersed in the sperm bio-hybrid cluster. Through micro-oscillation and magnetic field control, the bio-hybrid cluster is filled inside the magnetic microfluidic carrier robot.

[0022] Step 2: Introduction of sperm bio-hybrid magnetically controlled micro-nano robots The prepared microfluidic magnetically controlled bio-hybrid sperm robot 1 was introduced into the cavity of the uterus 8 of a 3D-printed female reproductive tract model 7 filled with physiological saline using a large syringe.

[0023] Step 3: Magnetic-driven and X-ray image-guided drug delivery (1) System configuration: Fix the female reproductive tract model 7 on the experimental table; configure the magnetic drive system: install a longitudinally magnetized neodymium iron boron permanent magnet 4 (diameter 20mm, height 10mm) at the end of the six-degree-of-freedom robotic arm 5; Imaging system configuration: Use the medical C-arm X-ray system 6 and adjust it to a left anterior oblique 30° position to avoid the robotic arm 5 interfering with the imaging field of view; set the X-ray dose rate to 25 mGy, which is within the commonly used clinical range; (2) Navigation control: Start the C-arm X-ray angiography system 6 to obtain real-time X-ray fluorescence fluoroscopic images; the operator or control algorithm identifies the position of the microfluidic magnetically controlled bio-mixed sperm robot 1 based on the images; by controlling the movement of the robotic arm 5, the permanent magnet 4 is rotated in the positive direction at a frequency of 1.5 Hz at a specific position above the model, generating a rotating magnetic field; this magnetic field applies magnetic torque to the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1, causing it to generate spin motion, thereby generating forward power; at the same time, by utilizing the unidirectionality of the Tesla valve, the internal sperm bio-mixed cluster does not overflow or flow out; (3) Precise drug delivery: By controlling the robotic arm 5 to drive the permanent magnet 4 along a predetermined path from the uterine cavity of the uterus 8 to the right fallopian tube 9, the microfluidic magnetically controlled bio-hybrid sperm robot 1 is magnetically coupled and rotated, generating directional traction and moving; the operator can obtain the cluster position throughout the process through X-ray image monitoring 10, such as Figure 3 a, Figure 3 As shown in b, the rotation direction of the magnetic field or the path of the robotic arm 5 can be adjusted in real time to correct the deviation; finally, the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 is precisely navigated to the target position of the right fallopian tube 9. (4) Drug release: After the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 reaches the target position, it reverses the external rotation field, causing the permanent magnet 4 to rotate in the opposite direction at a frequency of 1.5 Hz at a specific position above the model, so that the carrier robot reverses. The unidirectionality of the Tesla valve is used again to enable the rapid release of drug-loaded sperm biological mixed clusters, thereby achieving precise drug delivery. (5) Recovery of the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1: After the drug is accurately released, the rotation direction of the external rotation field is adjusted again so that the permanent magnet 4 rotates in the positive direction at a frequency of 1.5 Hz at a specific position above the model. According to the navigation control in step (2), the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 is navigated to the initial position in the uterine cavity 8 of the 3D printed female reproductive tract model 7. The magnetic device is turned off and the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 is taken out.

[0024] Example 2: Drug administration under ultrasound imaging monitoring The difference between this embodiment and Embodiment 1 is that an ultrasonic imaging system is used for real-time monitoring; a Siemens Acuson 14L5 ultrasonic probe is used to image the movement of the cluster; although X-ray contrast is clearer, ultrasonic imaging can also provide a sufficient contrast-to-noise ratio (CNR) for operators to monitor and navigate, and is suitable for radiation-sensitive or long-term monitoring scenarios.

[0025] Example 3: Drug administration under intelligent closed-loop automatic control The difference between this embodiment and Embodiment 1 is that, by combining machine learning and artificial intelligence image recognition algorithms, the motion trajectory characteristics of a large number of clinical images and the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot 1 of the bio-hybrid microrobot are used to train the robotic arm 5 and the control system with big data machine learning, automatically identify the cluster position, and adjust the magnetic field in real time for fully automatic navigation and closed-loop automatic control, thereby reducing the dependence on operators and radiation exposure.

[0026] The intelligent microfluidic magnetically controlled bio-hybrid sperm robot precise targeted drug delivery method described in this invention enables synchronous driving and positioning of a magnetic bio-hybrid robot based on X-ray image navigation in clinically relevant anatomical models. This solves the challenge of simultaneously achieving dynamism, visibility, and biocompatibility in the field of microrobots. By training an artificial intelligence image recognition algorithm, it achieves automatic identification of cluster positions and real-time adjustment of the magnetic field for fully automatic navigation. It boasts advantages such as high drug loading capacity, strong controllability, and good biocompatibility. It eliminates the need for magnetic field frequency changes for heating, ultrasonic fragmentation, or alteration of the lesion's chemical environment, ensuring safety and cleanliness. Especially in cancerous cases, it offers high operability, highly targeted drug delivery, and large drug loading capacity. Furthermore, the drug carrier is made from natural materials with high biodegradability and compatibility, and the manufacturing method is feasible. Its application prospects in high-precision targeted therapy for reproductive system diseases such as ovarian cancer, endometrial cancer, and endometriosis are very promising, providing a safe, efficient, and low-cost solution for the treatment of major gynecological diseases and reducing the suffering of cancer patients.

Claims

1. A method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot, characterized in that, Includes the following steps: (1) Fabrication of a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot: Magnetic nanoparticles are incorporated into the substrate through 3D micro-nano printing process to obtain a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot. Alternatively, a non-magnetic three-dimensional multi-helix Tesla valve polymer skeleton can be printed using 3D micro-nano printing technology, and then a magnetic metal film can be deposited on the surface through physical vapor deposition or sputtering to achieve magnetism, thereby producing a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot. (2) Preparation of bio-hybrid clusters: Bio-hybrid clusters composed of sperm cells and targeted drugs are prepared by electrostatic self-assembly; (3) Sperm bio-hybrid magnetically controlled micro-nano robot: The bio-hybrid cluster is injected into a three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot; or the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot structure is immersed in the bio-hybrid cluster, and the bio-hybrid cluster is filled inside the magnetic microfluidic carrier robot by micro-oscillation and magnetic field control, thereby obtaining a sperm bio-hybrid magnetically controlled micro-nano robot. (4) Microfluidic magnetically controlled bio-hybrid sperm robot introduction cluster: The prepared sperm bio-hybrid magnetically controlled micro-nano robots are introduced into the lesion area within the target biological cavity or anatomical model; (5) Magnetic drive and drug delivery: An external magnetic drive system is used to generate a rotating magnetic field to wirelessly drive the sperm bio-hybrid magnetically controlled micro-nano robot, causing it to spin along a specific coordinate axis; at the same time, a medical imaging system is used to locate and track the sperm bio-hybrid magnetically controlled micro-nano robot in real time; finally, the sperm bio-hybrid magnetically controlled micro-nano robot is guided to roll within the target cavity or anatomical model, and then guided to the lesion area to release drug-loaded sperm bio-hybrid clusters, thus achieving precise drug delivery; (6) Closed-loop automatic control: Train an image recognition artificial intelligence algorithm model to automatically identify the cluster location and adjust the magnetic field in real time for fully automatic navigation, reducing dependence on operators and radiation exposure.

2. The method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot according to claim 1, characterized in that, The magnetic nanoparticles mentioned in step (1) are superparamagnetic iron oxide nanoparticles with a particle size of 10-45 nm and a saturation magnetization of 10-30 emu / g.

3. The method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot according to claim 1, characterized in that, The magnetic metal film mentioned in step (1) is nickel or titanium or a mixture thereof, or other metal and non-metal magnetizable materials.

4. The method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot according to claim 1, characterized in that, The magnetic structure of the three-dimensional multi-helix Tesla valve magnetic microfluidic carrier robot obtained in step (1) is: a single-arm or multi-arm helical Tesla valve formed by spiral rotation along the central axis with a DNA-like structure. Among them, the multi-arm spiral Tesla valve can be combined at the top and bottom to form a single channel, or combined at one end to form a single-channel form or a multi-channel form.

5. The method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot according to claim 1, characterized in that, The sperm cells mentioned in step (2) are human sperm cells or treated allogeneic sperm cells, wherein the sperm cells are washed beforehand to remove seminal plasma and cryoprotectant before preparing the bio-hybrid microrobot cluster; The targeted drugs include small molecule inhibitors and large molecule drugs.

6. The method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot according to claim 1, characterized in that, The target biological cavity mentioned in step (4) is the female reproductive tract, and the lesion area includes specific parts of the uterus, fallopian tubes or ovaries.

7. The method for precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot according to claim 1, characterized in that, The external magnetic drive system described in step (5) includes a permanent magnet controlled by a robotic arm that performs rotational and translational motion; The frequency of the generated rotating magnetic field is 1-20 Hz, and the magnetic field strength is 5-20 mT. The medical imaging system is an X-ray fluorescence fluoroscopy imaging system or an ultrasound imaging system.

8. A system for achieving precise targeted drug delivery using an intelligent microfluidic magnetically controlled bio-hybrid sperm robot, characterized in that, It includes an intelligent microfluidic magnetically controlled bio-hybrid sperm robot preparation module, a magnetic drive module, a medical imaging module, and a control module.

9. The system according to claim 8, characterized in that, The intelligent microfluidic magnetically controlled bio-hybrid sperm robot preparation module is used to prepare intelligent microfluidic magnetically controlled bio-hybrid sperm robots through 3D micro-nano printing technology, or micro-nano printing with added physical vapor deposition or sputtering magnetic coating technology; it includes the preparation of magnetic induction base materials by 3D micro-nano printing technology, the fabrication of three-dimensional multi-helix Tesla valve magnetic microfluidic controlled carrier robot, and the post-processing of three-dimensional multi-helix Tesla valve magnetic microfluidic controlled carrier robot. The magnetic drive module is used to generate a rotating magnetic field that drives the movement of the cluster, and includes a permanent magnet and a drive device; wherein the permanent magnet is a robotic arm with multiple degrees of freedom. The medical imaging module is used for real-time imaging and positioning of the cluster, and it is a C-arm X-ray angiography system. The control module automatically identifies the cluster location based on feedback information received from the medical imaging module, combined with image recognition algorithms using machine learning and artificial intelligence. It then adjusts the magnetic field and robotic arm control in real time to perform fully automatic navigation and closed-loop automatic control, reducing reliance on operators and radiation exposure.

10. A bio-hybrid microrobot swarm, characterized in that, The system is prepared by the method described in any one of claims 1-7 or is the system described in any one of claims 8-9.

Images