Magnetic control medicine carrying robot for thrombus removal treatment

Abstract

The invention relates to the field of magnetic control micro-robots, in particular to a magnetic control drug-loaded robot for thrombus removal and treatment and a preparation method of the magnetic control drug-loaded robot. The magnetic control medicine carrying robot comprises a magnetic control robot body and a medicine carrying layer. The magnetic control robot body comprises a magnetic composite layer and a spiny skin layer. The medicine carrying layer is adhered to the surface of a magnetic composite layer of the magnetic control robot. The magnetic control medicine carrying robot carries the medicine carrying layer to be navigated to a target thrombus position in a blood vessel in a rolling or spiral movement mode, then a high-frequency rotating magnetic field is applied, the rolling movement or spiral movement speed of the magnetic control medicine carrying robot is increased accordingly, the spinous skin layer of the robot continuously rubs and collides with the thrombus, and medicine of the medicine carrying layer is released; the thrombus is broken, broken fresh platelets are taken away along with blood, fibrous protein is firmly attached to a spinous skin layer, thrombus fragments can be prevented from blocking other blood vessels, and the thrombus removing effect of the robot physical effect and drug therapy is achieved.

Description

Technical Field

[0001] This invention relates to the field of magnetically controlled microrobots, and in particular to a magnetically controlled drug-carrying robot for thrombus removal therapy and its preparation method. Background Technology

[0002] Epidemiological data shows that approximately 80% of cardiovascular events are closely related to thrombosis. The "targeted" occlusion characteristic of thrombi makes them the core pathological basis for the high mortality rate of cardiovascular diseases. Traditional methods of thrombus removal include oral thrombolysis, mechanical thrombectomy, and catheter-based thrombolysis. Although effective, these methods have many limitations. For example, oral thrombolysis requires long-term use and carries the risk of bleeding. Mechanical thrombectomy and catheter-based thrombolysis are continuous interventional devices. Due to their inherent bending stiffness, they inevitably bend when passing through blood vessels with small bending radii, affecting their ability to reach difficult-to-access areas. Furthermore, they require high levels of skill from physicians and carry the risk of thrombus injury.

[0003] In recent years, researchers have begun exploring cordless interventional robots beyond traditional actuation mechanisms. Among these, magnetic control technology has seen rapid development due to its high energy density, good biocompatibility, and safe penetration characteristics. For example, existing technologies disclose a clustered magnetic micro / nanorobot capable of loading thrombolytic drugs; and a helical microrobot capable of high-performance movement in blood vessels. However, the aforementioned clustered magnetic micro / nanorobots exhibit severe aggregation and random bioadhesion in high-ionic-strength blood environments; the high-performance helical microrobot in blood vessels, being a pure hard magnetic helix, poses a risk of vascular damage during high-speed movement and lacks drug-loading capabilities. Therefore, given the current shortcomings of magnetically controlled microrobots, improvements are necessary. Summary of the Invention

[0004] To address the shortcomings of existing thrombus removal technologies, this invention provides a magnetically controlled drug-carrying robot for thrombus removal therapy. It aims to solve the technical challenges of poor precision, low removal efficiency, and high invasiveness associated with traditional treatment methods.

[0005] To achieve the above objectives, the present invention provides the following solution: One of the technical solutions of this invention is a method for preparing a magnetically controlled robot, comprising the following steps: Step 1: Mix the magnetic particles with the polymer, spread them in a mold, and cure to obtain a magnetic composite layer; Step 2: Mix the magnetic particles and the polymer, and lay them on the surface of the magnetic composite layer to obtain a mixture layer; apply a magnetic field under the magnetic composite layer to induce the mixture layer to form a spiky structure, and then solidify to form a spiky skin layer to obtain a magnetic composite layer-spiky skin layer composite device. Step 3: Perform anisotropic magnetic encoding on the magnetic composite layer-spiky skin layer composite device to obtain the magnetically controlled robot.

[0006] The second technical solution of the present invention is a magnetically controlled robot prepared using the above-described preparation method.

[0007] The third technical solution of the present invention is a magnetically controlled drug-carrying robot, comprising the above-mentioned magnetically controlled robot and a drug-carrying layer; the drug-carrying layer is adhered to the surface of the magnetic composite layer of the magnetically controlled robot.

[0008] The fourth technical solution of the present invention is the application of the above-mentioned magnetically controlled robot or the above-mentioned magnetically controlled drug-carrying robot in the preparation of drugs or medical devices for treating and clearing thrombi or foreign objects in cavities.

[0009] Compared with the prior art, the present invention has the following beneficial effects: The magnetically controlled drug-carrying robot of this invention carries a drug-loaded layer and navigates to the target thrombus location in a blood vessel by rolling or spiraling motion. Then, a high-frequency rotating magnetic field is applied, which increases the speed of the rolling or spiraling motion of the magnetically controlled drug-carrying robot. The continuous friction and collision between the robot's spiky skin layer and the thrombus, along with the release of the drug from the drug-loaded layer, causes the thrombus to break up. The broken fresh platelets are carried away by the blood, and fibrin adheres firmly to the spiky skin layer, which can prevent thrombus fragments from blocking other blood vessels. This achieves the dual effect of clearing thrombi through the physical action of the robot and drug treatment. Attached Figure Description

[0010] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0011] Figure 1 This is a schematic diagram of the magnetically controlled robot prepared according to Embodiment 1 of the present invention; Figure 2 This is a schematic diagram of the magnetically controlled drug-carrying robot prepared in Embodiment 2 of the present invention; Figure 3 This is a schematic diagram of two motion modes of the magnetically controlled robot prepared in Embodiment 1 of the present invention under a magnetic field; Figure 4 The graph shows the relationship between magnetic field strength, rotation frequency, and average velocity of the magnetically controlled robot prepared in Embodiment 1 of the present invention. Figure 5 A comparison chart showing the success rate of the magnetically controlled robot prepared in Example 1 of the present invention, compared with a smooth robot with barbed skin, in passing through cavities of different materials and shapes within 3 minutes; Figure 6 A comparison of the average speed of the magnetically controlled robot prepared in Example 1 of the present invention and a smooth robot with barbed skin moving in pipes of different materials; Figure 7 The drug release curve of the drug-loaded layer prepared in Example 2 of this invention; Figure 8 This is a graph showing the mass change of the drug-loaded layer prepared in Example 2 of the present invention in a gastric fluid environment; Figure 9 This is a demonstration image showing the fragmentation effect of the magnetically controlled drug-carrying robot prepared in Embodiment 2 of the present invention in a liquid-filled environment; Figure 10 This image shows a demonstration of the magnetically controlled drug-carrying robot, prepared in Example 2 of the present invention, navigating and clearing thrombi in a model of the middle cerebral artery.

[0012] Figure 1-2 In the middle, 11-magnetic composite layer, 12-spiky skin layer, 13-drug-loaded layer. Detailed Implementation

[0013] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0014] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0015] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0016] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be obvious to those skilled in the art. This specification and embodiments are merely exemplary.

[0017] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0018] Thrombotic diseases have become a major public health problem threatening human health, ranking among the top in both incidence and mortality. Thrombosis not only directly leads to vascular obstruction, causing fatal diseases such as acute myocardial infarction, stroke, and pulmonary embolism, but also causes post-thrombotic syndrome, severely impacting patients' quality of life. Traditional thrombectomy methods mainly include thrombolysis and mechanical thrombectomy, but both have significant limitations: thrombolysis is slow to take effect, carries a high risk of bleeding, and is only suitable for certain patients; mechanical thrombectomy is complex to perform, may not completely remove thrombi, carries a high risk of vascular damage, and is particularly unsuitable for smaller vessels. Therefore, developing a novel treatment technology that can precisely, efficiently, and safely remove thrombi is of significant clinical and social value for improving patient prognosis and reducing mortality.

[0019] This invention's magnetically controlled drug-carrying robot utilizes an external magnetic field for precise navigation, enabling it to reach tiny blood vessels and complex cavities that are difficult for traditional instruments to access, achieving precise localization of thrombi. Through its drug delivery system design, it can achieve targeted drug release at the thrombus site, improving thrombolysis efficiency while significantly reducing the risk of systemic bleeding. Using magnetically controlled drive technology, the robot can generate multiple motion modes, effectively stripping and removing thrombi, avoiding damage to the vessel wall caused by traditional mechanical thrombectomy. This invention provides a novel minimally invasive treatment method for cavity foreign body diseases, not only achieving precise thrombus removal but also having broad applicability to the diagnosis and treatment of other cavity diseases, demonstrating significant clinical application prospects and promotional value.

[0020] The first aspect of this invention provides a method for manufacturing a magnetically controlled robot, comprising the following steps: Step 1: Mix the magnetic particles with the polymer, spread them in a mold, and cure to obtain a magnetic composite layer; Step 2: Mix the magnetic particles and the polymer, and lay them on the surface of the magnetic composite layer to obtain a mixture layer; apply a magnetic field under the magnetic composite layer to induce the mixture layer to form a spiky structure, and then solidify to form a spiky skin layer to obtain a magnetic composite layer-spiky skin layer composite device. Step 3: Perform anisotropic magnetic encoding on the magnetic composite layer-spiky skin layer composite device to obtain the magnetically controlled robot.

[0021] In a preferred embodiment of the present invention, in step 1, the magnetic particles include neodymium iron boron (NdFeB); the polymer is polydimethylsiloxane (PDMS); the mass ratio of the magnetic particles to the polymer is (1~5):1. When the mass ratio of the magnetic particles to the polymer is >5:1, the magnetic composite layer becomes less flexible and more brittle. When the mass ratio of the magnetic particles to the polymer is <1:1, the magnetic particle content is low, the residual magnetization after encoding is low (<5mT), and the response to the magnetic field is weak, making it unsuitable for high-responsive applications requiring thrombus fragmentation. Therefore, when the mass ratio of the magnetic particles to the polymer is between (1~5):1, the magnetically controlled robot can simultaneously possess both good flexibility and high magnetic field responsiveness. The curing temperature is 60~90℃, and the time is 2~4h. Too low a curing temperature or too short a time will affect the degree of cross-linking of the robot. Within this range, the curing effect of the robot is optimal. The thickness of the magnetic composite layer is 0.1~0.5mm. When the thickness of the magnetic composite layer is >0.5mm, the flexibility of the robot deteriorates.

[0022] The present invention also tested the aliphatic aromatic random copolyester (Ecoflex) as a polymer. The results showed that the mechanical strength and tear resistance of the robot made by Ecoflex were not as good as those of PDMS, and its own stiffness was low. It was difficult to maintain the preset motion shape under high frequency magnetic field, thus affecting the subsequent thrombus fragmentation efficiency. Therefore, Ecoflex was no longer used in the future, and PDMS was used instead.

[0023] In some embodiments of the present invention, the magnetic composite layer has a length of 5-20 mm and a width of 1-10 mm.

[0024] In a preferred embodiment of the present invention, in step 2, the magnetic particles include neodymium iron boron and / or iron powder; the polymer is polydimethylsiloxane; the mass ratio of the magnetic particles to the polymer is 3:1; the curing temperature is 60~90℃ and the time is 2~4h.

[0025] In a preferred embodiment of the present invention, the magnetic particles comprise neodymium iron boron and iron powder; the mass ratio of neodymium iron boron to iron powder and polymer is 1:2:1.

[0026] In step 2 of this invention, a magnetic powder-assisted method of "single material step-by-step molding" is used. A magnetic field strength is applied directly below the mold (the mold filled with a magnetic composite layer) to form an uncured spiky skin layer. The length of the spiky skin can be controlled by controlling the magnetic field strength.

[0027] In a preferred embodiment of the present invention, in step 3, the magnetic composite layer-spiky skin layer composite device is spirally wound onto a non-magnetic rod with water-soluble adhesive, placed in a single-fill magnetizer, and an electric field is applied to directionally magnetize the magnetic particles to complete anisotropic magnetic encoding; the water-soluble adhesive is then removed to obtain the magnetically controlled robot.

[0028] A second aspect of the present invention provides a magnetically controlled robot prepared using the above-described preparation method.

[0029] The magnetically controlled robot consists of a magnetic composite layer and a barbed skin layer. The magnetic composite layer is used for precise magnetic navigation and ensures the robot's excellent flexibility, avoiding the risk of vascular damage. The barbed skin layer is used to enhance the robot's interaction pressure with blood clots and the robot's movement flexibility.

[0030] A third aspect of the present invention provides a magnetically controlled drug-carrying robot, comprising the aforementioned magnetically controlled robot and a drug-carrying layer; the drug-carrying layer is adhered to the surface of the magnetic composite layer of the magnetically controlled robot.

[0031] The drug-loaded layer is a drug-loaded hydrogel with polyvinyl alcohol (PVA) as its backbone structure.

[0032] In a preferred embodiment of the present invention, the method for preparing the drug-loaded layer includes the following steps: Sodium alginate and glycerol were added to an aqueous solution of polyvinyl alcohol and mixed well, and then the drug was added and mixed well to obtain a drug-loaded precursor. The drug-loaded precursor was placed in a mold, and the drug-loaded layer was obtained by physical cross-linking-freeze cycling method.

[0033] This invention also experimented with adding a certain amount of gelatin along with sodium alginate and glycerol during the preparation of the drug-loaded precursor. The results showed that the structural integrity of the drug-loaded layer prepared with added gelatin was inferior to that without gelatin. Furthermore, gelatin is a protein and is easily degraded by enzymes such as pepsin; adding gelatin introduces new uncertainties. Therefore, this invention did not choose to add gelatin in the preparation of the drug-loaded layer.

[0034] In a preferred embodiment of the present invention, the concentration of polyvinyl alcohol in the drug-loaded precursor is 0.02~0.08 g / mL, the concentration of sodium alginate is 0.02 g / mL, the concentration of glycerol is 0.05 g / mL, and the concentration of the drug is 0.04~0.12 g / mL; the drug is a thrombolytic drug; in a preferred embodiment of the present invention, the physical cross-linking-freeze cycling method specifically involves freezing at -20℃ for 3~6 h, thawing at room temperature, and repeating 4~5 times; the thickness of the drug-loaded layer is 0.2~0.4 mm.

[0035] The magnetically controlled drug-carrying robot of the present invention comprises a drug-carrying layer, a magnetic composite layer, and a spiky skin layer arranged sequentially.

[0036] The fourth aspect of the present invention provides the application of the above-described magnetically controlled robot, or the above-described magnetically controlled drug-carrying robot, in the preparation of drugs or medical devices for treating and clearing thrombi or foreign bodies in cavities.

[0037] The method of using the magnetically controlled drug-carrying robot of the present invention to remove thrombi is as follows: (1) Injection of a magnetically controlled drug delivery robot, which includes preloading the magnetically controlled drug delivery robot into a catheter and then inserting it into the blood vessel via the catheter. (2) The motion of the magnetically controlled drug-carrying robot includes the rolling motion of the magnetically controlled drug-carrying robot formed by an external rotating magnetic field (magnetic field strength of 5~35mT, magnetic field frequency of 0~10Hz); (3) The effect of the magnetically controlled drug-carrying robot on the thrombus includes the application of a high-frequency rotating magnetic field, which increases the speed of the magnetically controlled drug-carrying robot. The robot's spiky skin layer and the thrombus are constantly rubbed and collided, and the drug in the drug-carrying layer is released, causing the thrombus to break up. The broken fragments are firmly attached to the spiky skin layer, which can prevent the thrombus fragments from blocking other blood vessels, thus achieving the dual effect of clearing the thrombus through the physical action of the robot and drug treatment. (4) Recovery of the magnetically controlled drug delivery robot. Recovery includes returning to the vicinity of the catheter by movement. Under the action of the magnetic field, the magnetically controlled drug delivery robot can be recovered through the catheter.

[0038] The magnetically controlled drug delivery robot of the present invention has the following advantages: 1. Security Compared to conventional rigid magnetically controlled robots, the magnetically controlled robot of this invention uses polydimethylsiloxane (PDMS), a polymer with excellent biocompatibility. The final magnetic composite layer has a magnetic particle to PDMS mass ratio of 3:1. At this ratio, the robot maintains both high magnetic responsiveness and flexibility, thus fundamentally eliminating the risk of perforation. Furthermore, the magnetic composite layer and the spiky skin in the magnetically controlled drug delivery robot involve a single-material stepwise molding method. That is, by using the same polymer as the magnetic composite layer, spiky structures are cultivated on the surface, so that the magnetic composite layer and the spiky skin layer are integrated at the molecular scale, thereby avoiding interface problems and assembly difficulties, and preventing the risk of micro-spiky structures falling off during high-speed robot movement.

[0039] 2. Highly efficient cavity passage Traditional smooth microrobots are prone to "wall slippage" or "stuckness" in tortuous cavities or slippery tissue interfaces. The spiky skin protrusions of this invention, driven by a magnetic field, can periodically "bounce" against the tube wall, preventing robot jamming and improving passage efficiency within the cavity. This invention verified the robot's passage rate in simulated cavities of different shapes and lengths ≥15cm ("O", "U", and "I" types). In 10 tests, the passage rate was 100% within three minutes. Simultaneously, the movement speed of this invention was compared with that of previous smooth microrobots on different material surfaces (glass, acrylic, and gastric tissue). The test results showed that the magnetically controlled robot of this invention has a higher movement speed than the smooth microrobot. Specifically, on glass surfaces, the average movement speed of the magnetically controlled robot of this invention reaches 126.9mm / s, significantly higher than the control group.

[0040] 3. Dual-mode thrombus clearance using drug therapy and physical therapy This invention features spiky skin protrusions on the surface of a magnetically controlled drug-carrying robot. When an external high-frequency rotating magnetic field is applied, the robot rapidly rolls or spirals forward. Under the action of "microscopic high-frequency hammering + scraping," the spiky skin quickly breaks down the thrombus network structure, exposing the fresh platelet / fibrin interface. Simultaneously, the thrombolytic drugs (such as urokinase, nattokinase, rt-PA, etc.) locally released from the drug-carrying layer of this invention directly act on the fresh wound, achieving a synergistic effect of "deep drug penetration - physical cell wall disruption." Furthermore, the drug-carrying layer exhibits excellent biocompatibility and can be used as a drug carrier for the treatment of other diseases (such as gastrointestinal diseases).

[0041] 4. Low cost The material preparation process is simple (only involving the ratio control of neodymium iron boron and polymer (PDMS), which can be mass-produced and significantly reduce production costs. The prepared magnetically controlled robot can be used not only for thrombus removal, but also for the removal or treatment of foreign bodies in other cavities. It has broad application prospects in the fields of precision interventional medicine in the future.

[0042] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field, and the reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0043] The average particle size of the neodymium iron boron powder used in this embodiment of the invention is 5 μm; the ratio of polydimethylsiloxane to curing agent is 10:1.

[0044] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0045] Example 1 This embodiment provides a method for fabricating a magnetically controlled robot for thrombus removal therapy. The robot's speed can be controlled by adjusting the frequency of the rotating magnetic field. A schematic diagram of the magnetically controlled robot is shown below. Figure 1 As shown: Figure 1 In the middle, 7-magnetic composite layer, 8-spiky skin layer. The fabrication method of this magnetically controlled robot includes the following steps: S1. Preparation of magnetic composite layer: Neodymium iron boron (NdFeB) and polydimethylsiloxane (PDMS) are physically blended at a mass ratio of 3:1 and evenly spread in an acrylic mold with a thickness of 0.2 mm; excess material is scraped off with a blade to ensure a smooth surface, and then cured at 80℃ for 3 hours to obtain a magnetic composite layer with a thickness of 0.2 mm.

[0046] S2. Preparation of the magnetic composite layer-spiky skin layer composite device: Using the magnetic composite layer prepared in step S1 as the substrate, neodymium iron boron, iron powder and polydimethylsiloxane (PDMS) are physically blended in a mass ratio of 1:2:1 to obtain a spiky skin precursor mixture; this mixture is directly coated onto the surface of the magnetic composite layer obtained in step S1, with the thickness limited by a 0.1 mm acrylic mold, and a 30 mT magnetic field is applied directly below the mold to induce the formation of an uncured spiky structure (50-500 μm); the entire assembly is then placed at 80℃ for 3 h for thermal curing, and then rapidly cut to a size of 7.5 × 15 mm using a high-precision laser beam to obtain the magnetic composite layer-spiky skin layer composite device.

[0047] S3. Magnetic Programming: The magnetic composite layer-spiky skin layer composite device prepared in step S2 is spirally wound onto a non-magnetic rod with a diameter of 5 mm using water-soluble adhesive. It is then placed in a single-charge magnetizer, with the openings at both ends of the magnetic composite layer-spiky skin layer composite device at a 45° angle to the magnetic field direction. This magnetic field is a pulsed magnetic field with a peak value of 2.5 T, and the magnetization time is 2-3 ms. After magnetization, the NdFeB particles are instantaneously and directionally magnetized, completing anisotropic magnetic encoding. Subsequently, the robot is peeled off, and the device is soaked in deionized water for 30 min to dissolve residual adhesive, thus obtaining a magnetic composite layer-spiky skin layer composite device with precise magnetization direction. In this step, the spiky skin is located on the periphery, and the magnetic composite layer adheres to the non-magnetic rod. The final result is a magnetically controlled robot with dimensions of 15 × 7.5 × 0.6 mm (see schematic diagram). Figure 1 (As shown).

[0048] The magnetically controlled robot prepared in this embodiment is placed in an artificial cavity for navigation, such as... Figure 3 As shown. The initial state without a magnetic field, the rolling state under a rotating magnetic field (rotation frequency 1Hz, magnetic field strength 15mT), and the spiral state (as shown). Figure 3 (As shown in Figures 14, 16, and 17). Figure 3It can be seen that when there is no magnetic field in the artificial cavity 15 with an inner diameter of 4.5 mm, the magnetically controlled robot is in the initial state 14. When a rotating magnetic field is applied, it generates rolling motion 16 and spiral motion 17 (the direction indicated by the arrow is the direction of movement of the magnetically controlled robot).

[0049] The speed of the magnetically controlled robot prepared in Example 1 can be controlled by controlling the frequency of the rotating magnetic field. Figure 4 This is a graph showing the relationship between magnetic field strength, rotation frequency, and average speed for the magnetically controlled robot prepared in Example 1. In this invention, the average speed of the magnetically controlled robot was tested on an acrylic substrate under magnetic field strengths of 5mT, 15mT, and 25mT, and magnetic field rotation frequencies of 0.5Hz, 1Hz, 1.5Hz, 2Hz, 4Hz, 6Hz, 8Hz, and 10Hz for rolling the same distance. The curves showing the change in average speed versus rotation frequency were plotted, resulting in the graph showing the relationship between magnetic field strength, rotation frequency, and average speed. Figure 4 It can be seen that the average speed of the magnetically controlled robot gradually increases with the increase of the magnetic field rotation frequency, reaches a peak, and then saturates. Moreover, the stronger the magnetic field strength, the higher the peak speed. The purpose of this test is to screen the magnetic field conditions to obtain the optimal magnetic field strength and the optimal rotation frequency. As shown in the figure, the average speed is the highest at 25mT and 3Hz, which is the optimal magnetic field condition.

[0050] To highlight the motion performance of the magnetically controlled robot of the present invention, it was compared with a conventional smooth robot that is flexible but without barbs (the preparation method of the smooth robot without barbs differs from that of Example 1 only in that the preparation of the barb layer is omitted). Figure 5 This image compares the success rate of the magnetically controlled robot prepared in this embodiment with that of a smooth robot with barbed skin, navigating cavities of different materials and shapes within 3 minutes. The invention tested the pass rate of the magnetically controlled robot within 3 minutes at a magnetic field strength of 15 mT and a magnetic field rotation frequency of 1 Hz, passing through "O"-shaped silicone tubes, "U"-shaped glass tubes, and "I"-shaped acrylic tubes (all ≥15 cm in length), with 10 tests per group. Figure 5 It can be seen that the magnetically controlled robot with barbed skin of the present invention has a 100% pass rate in "O"-shaped silicone tube, "U"-shaped glass tube, and "I"-shaped acrylic tube, indicating that the introduction of the barbed skin layer structure greatly improves the flexibility of robot movement, avoids robot jamming, and improves the pass-through efficiency in the cavity. Figure 6 This invention presents a comparison of the average speed of the magnetically controlled robot prepared in this embodiment with that of a smooth robot with barbed skin, moving through pipes of different materials. The invention tested the average speed of the magnetically controlled robot as it traversed an acrylic pipe, a glass pipe, and stomach tissue of the same length (80 mm) under a magnetic field strength of 15 mT and a magnetic field rotation frequency of 1 Hz. Figure 6It is evident that the magnetically controlled robot with barbed skin of this invention exhibits significantly higher average speeds than the smooth robot without barbs on three interfaces: acrylic tube, glass tube, and gastric tissue. The performance on the glass surface is particularly outstanding, with the robot achieving an average speed of 126.9 mm / s, far exceeding the control group. Even on the slippery gastric tissue surface, no "wall-adhering slippage" phenomenon was observed, maintaining a high-speed propulsion of 114.2 mm / s. This not only verifies the significant improvement in gripping-detachment efficiency brought about by the barbed structure but also highlights the robot's flexible and efficient movement advantages in complex biological environments.

[0051] Example 2 This embodiment provides a method for fabricating a magnetically controlled drug-carrying robot. A schematic diagram of the structure of the magnetically controlled drug-carrying robot is shown below. Figure 2 As shown in the figure: 11-magnetic composite layer, 12-spiky skin layer, 13-drug-carrying layer; the drug-carrying layer is bonded to the magnetic composite layer by the adhesive properties of the hydrogel. This magnetically controlled drug-carrying robot is based on the above magnetically controlled robot and introduces a drug-carrying layer 13, in which methylene blue is selected as the simulated drug for the following reasons: (1) Methylene blue has a strong characteristic absorption peak, which is easy to detect; (2) It is highly visible and its distribution and release process in the hydrogel can be observed with the naked eye. The preparation method of this magnetically controlled drug-carrying robot is as follows: Steps S1 to S3: Same as steps S1 to S3 in Example 1.

[0052] Step S4: Preparation of drug-loaded hydrogel film: 1.2 g of polyvinyl alcohol (PVA) was dispersed in 20 mL of deionized water and stirred at 90 °C for 3 h until completely dissolved. The solution was then allowed to cool naturally to obtain a PVA solution. 0.4 g of sodium alginate (SA) and 1 g of glycerol (Gly) were added sequentially to the PVA solution, and the mixture was stirred at 50 °C for 2 h to ensure complete dissolution. Subsequently, 0.06 g of methylene blue was added, and the mixture was stirred at room temperature for 2 h to uniformly color the solution, yielding a methylene blue-loaded hydrogel precursor. The precursor was poured into a 0.2 mm high silica gel mold, and a physical cross-linking-freeze cycle method was used (freezing at -20 °C for 6 h, thawing at room temperature, repeated 5 times). After demolding, a drug-loaded layer with a thickness of 0.2 mm was obtained. This drug-loaded layer can be directly bonded to a magnetically controlled robot to obtain a magnetically controlled drug-loaded robot.

[0053] The drug delivery layer of this magnetically controlled drug delivery robot can release drugs. Figure 5The graph shows the cumulative drug release curve of the drug-loaded layer. An in vitro release test was conducted: a 0.2 mm thick drug-loaded hydrogel containing 4.015 mg of methylene blue was placed in 15 mL of deionized water and shaken at 37°C and 100 rpm to simulate the in vivo environment. 1 mL samples were taken at 0, 2, 5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, and 300 min, and an equal volume of deionized water was immediately added. The methylene blue concentration was calculated using the absorbance at 607 nm (blank correction). The cumulative release of methylene blue was calculated using the following formula: Qn=Cn×V0+(C1+C2+……+Cn-1)×V Where Qn is the cumulative release amount at the nth sampling, Cn is the drug concentration at the nth sampling, V0 is the initial volume of the release medium, and V is the volume of each sampling. The cumulative release amount is calculated to be 3.544 mg, and the cumulative release percentage is 88.27%. A cumulative release curve is then plotted, as shown below. Figure 7 As shown. By Figure 7 It can be seen that the drug-loaded layer can complete 88.27% release within 5 hours, with a burst release of 20% in the first 0.5 hours, followed by the first-order kinetic diffusion control stage, which is suitable for local drug delivery, indicating that the drug-loaded layer of the present invention has good drug release efficiency.

[0054] The drug delivery layer of this magnetically controlled drug delivery robot can remain stable in the gastric fluid environment. Figure 8 This is a graph showing the mass change of the drug-loaded hydrogel layer in a gastric fluid environment. The specific experimental procedure included: The procedure is the same as step S4, except that the ratio of polyvinyl alcohol (PVA) to sodium alginate (SA) is different. A hydrogel with a mass ratio of PVA to SA of (1~4):1 and a thickness of 0.2 mm is prepared and placed in 15 mL of commercially available enzyme-containing gastric juice. The mixture is then subjected to constant temperature shaking at 37°C and 100 rpm to simulate the in vivo environment. Weighing and recording are performed at 0, 10, 30, 60, 100, 150, 210, 280, 360, 450, and 550 min. A graph showing the mass change of the drug-loaded hydrogel layer in the gastric juice environment is plotted, and the influence of the gastric juice on the hydrogel's network structure is observed. Figure 8 As shown. By Figure 8 It can be seen that Figure 8 The results showed that the overall weight of the hydrogel remained stable without significant fluctuations. When the mass ratio of polyvinyl alcohol (PVA) to sodium alginate (SA) was 3:1, the hydrogel weight decreased only slightly from 1.4265g to 1.4113g, a loss of less than 1.1%, and the appearance remained intact without significant deformation. This result confirms that the drug-loaded hydrogel possesses excellent stability in physiological environments, making it suitable not only for vascular interventional therapy but also for safe local drug delivery in gastrointestinal diseases.

[0055] The efficacy of the magnetically controlled drug-carrying robot (cut to size 15×7.5×0.8mm) prepared in Example 2 in clearing thrombi in a liquid-filled environment was verified as follows: The magnetically controlled drug-carrying robot was loaded into a sterile centrifuge tube (5 ml) filled with phosphate-buffered saline (PBS) to simulate the blood pH, osmotic pressure, and inorganic ion environment. A 0.6679 g, 1 cm long simulated thrombus was added. The robot was guided to the thrombus location by an external permanent magnet magnetic field generator. A rotating magnetic field with a frequency of 3 Hz and a magnetic field strength of 25 mT was applied to make the robot's spiky skin layer continuously rub and collide with the thrombus. The thrombus fragmentation was observed after 10 minutes. Figure 9 This is a demonstration image showing the fragmentation effect of the magnetically controlled drug-carrying robot of the present invention in a liquid-filled environment, as shown. Figure 9 As shown, after the robot reached the thrombus site, it was able to break up a 1cm long, 0.6679g thrombus 18 under the influence of a 25mT, 3Hz rotating magnetic field for only 10 minutes; the liquid in the centrifuge tube turned dark red 19, indicating that the thrombus was efficiently disintegrated. After collecting the residue, the largest fragment 20 was only 2.5mm in diameter, fully demonstrating that the magnetically controlled drug-carrying robot has excellent thrombolytic efficiency in the body fluid environment.

[0056] The magnetically controlled drug-carrying robot (cut to size 10×3×0.8mm) prepared in Example 2 was tested for navigation and thrombus removal in a middle cerebral artery model, as detailed below: A simulated thrombus is pre-injected into a purchased 3D-printed model of the middle cerebral artery. A magnetically controlled drug-carrying robot is pre-loaded into a catheter and inserted into the vascular model via catheter intervention. The robot is guided by an external permanent magnet magnetic field generator. Through helical precession under a rotating magnetic field, the robot can enter the vascular branch and reach the thrombus location. By applying a rotating magnetic field with a frequency of 3Hz and a magnetic field strength of 25mT, the movement speed of the magnetically controlled drug-carrying robot increases. The robot's spiky skin layer continuously rubs and collides with the thrombus, causing the thrombus to break up, and the thrombus fragments can be carried by the spiky skin layer. Afterwards, it returns to the vicinity of the catheter, and under the influence of the magnetic field, the magnetically controlled drug-carrying robot can be retrieved through the catheter. Figure 6 This is a schematic diagram demonstrating the navigation and thrombus removal of the magnetically controlled drug-carrying robot in a middle cerebral artery model, as shown in the image. Figure 6As shown, the magnetically controlled drug-carrying robot 21 is guided by an external permanent magnet magnetic field generating device. After spiral precession under the rotating magnetic field, the robot can enter the blood vessel branch and reach the thrombus location 22. By applying a rotating magnetic field with a frequency of 3Hz and a magnetic field strength of 25mT, the movement speed of the magnetically controlled drug-carrying robot increases accordingly. The robot's spiky skin layer rubs and collides with the thrombus continuously 23. After 120s, the thrombus breaks, leaving only blood and thrombus fragments, of which the thrombus fragments are attached to the spiky skin layer. Then, under the action of the magnetic field, it returns along the original path 24 and returns to the vicinity of the catheter 25, where the magnetically controlled drug-carrying robot is retrieved.

[0057] The drug-loaded layer in this invention has been verified to have good release efficiency. In addition, it has good mechanical properties and can exist stably in other liquid environments (gastric acid). Therefore, it can also be used for the removal and treatment of foreign bodies in other cavities.

[0058] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for manufacturing a magnetically controlled robot, characterized in that, Includes the following steps: Step 1: Mix the magnetic particles with the polymer, spread them in a mold, and cure to obtain a magnetic composite layer; Step 2: Mix the magnetic particles and the polymer, and lay them on the surface of the magnetic composite layer to obtain a mixture layer; apply a magnetic field under the magnetic composite layer to induce the mixture layer to form a spiky structure, and then solidify to form a spiky skin layer to obtain a magnetic composite layer-spiky skin layer composite device. Step 3: Perform anisotropic magnetic encoding on the magnetic composite layer-spiky skin layer composite device to obtain the magnetically controlled robot.

2. The method for manufacturing a magnetically controlled robot according to claim 1, characterized in that, In step 1, the magnetic particles include NdFeB; the polymer is polydimethylsiloxane and / or aliphatic aromatic random copolyester; the mass ratio of the magnetic particles to the polymer is (1~5):1; the curing temperature is 60~90℃ and the time is 2~4h; the thickness of the magnetic composite layer is 0.1~0.5mm.

3. The method for manufacturing a magnetically controlled robot according to claim 1, characterized in that, In step 2, the magnetic particles include neodymium iron boron and / or iron powder; the polymer is polydimethylsiloxane; the mass ratio of the magnetic particles to the polymer is 3:1; the curing temperature is 60~90℃ and the time is 2~4h.

4. The method for manufacturing a magnetically controlled robot according to claim 1, characterized in that, In step 3, the magnetic composite layer-spiky skin layer composite device is spirally wound onto a non-magnetic rod with water-soluble glue, placed in a single-fill magnetizer, and an electric field is applied to magnetize the magnetic particles in a specific direction, thus completing the anisotropic magnetic encoding. Remove the water-soluble glue to obtain the magnetically controlled robot.

5. A magnetically controlled robot prepared by the preparation method according to any one of claims 1 to 4.

6. A magnetically controlled drug-carrying robot, characterized in that, It includes the magnetically controlled robot as described in claim 5 and a drug-loaded layer; the drug-loaded layer is adhered to the surface of the magnetic composite layer of the magnetically controlled robot.

7. The magnetically controlled drug-carrying robot according to claim 6, characterized in that, The method for preparing the drug-loaded layer includes the following steps: Sodium alginate and glycerol were added to an aqueous solution of polyvinyl alcohol and mixed well, and then the drug was added and mixed well to obtain a drug-loaded precursor. The drug-loaded precursor was placed in a mold, and the drug-loaded layer was obtained by physical cross-linking-freeze cycling method.

8. The magnetically controlled drug-carrying robot according to claim 7, characterized in that, The concentration of polyvinyl alcohol in the drug-loaded precursor is 0.02~0.08 g / mL, the concentration of sodium alginate is 0.02 g / mL, the concentration of glycerol is 0.05 g / mL, and the concentration of the drug is 0.04~0.12 g / mL; the drug is a thrombolytic drug.

9. The magnetically controlled drug-carrying robot according to claim 7, characterized in that, The physical cross-linking-freeze cycle method specifically involves freezing at -20℃ for 3~6 hours, thawing at room temperature, and repeating this process 4~5 times; the thickness of the drug-loaded layer is 0.2~0.4 mm.

10. The use of the magnetically controlled robot as described in claim 5, or the magnetically controlled drug-carrying robot as described in any one of claims 6 to 9, in the preparation of drugs or medical devices for treating and clearing thrombi or foreign bodies in cavities.

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