Magnetic responsive micro-robot tissue penetration control method and system

Abstract

The application relates to the technical field of biomedical engineering, and discloses a magnetic response micro-robot tissue penetration control method and system. The method comprises the following steps: S1, placing a magnetic response micro-robot in a target biological environment to be penetrated; S2, applying a main tumbling magnetic field to drive the magnetic response micro-robot to perform tumbling motion along a main tumbling plane; S3, on the basis of the main tumbling magnetic field, superimposing a periodic oscillation magnetic field component along a third axis direction outside the main tumbling plane to form a three-dimensional wave magnetic field; and S4, using the three-dimensional wave magnetic field to drive the magnetic response micro-robot to generate posture oscillation along the third axis direction in the tumbling motion process, so as to modulate the normal contact state between the magnetic response micro-robot and the target biological environment, increase the effective contact area and / or enhance the friction coupling, thereby inhibiting the slip and realizing the penetration movement of the magnetic response micro-robot in the target biological environment.

Description

Technical Field

[0001] This application relates to the field of biomedical engineering technology, specifically to a method and system for controlling tissue penetration by a magnetically responsive microrobot. Background Technology

[0002] In recent years, magnetically driven microrobots have become an important research direction for targeted delivery, local treatment, minimally invasive intervention, and in vivo diagnosis and treatment due to their advantages such as remote contactless manipulation, strong tissue penetration potential, and broad biomedical application prospects. Compared with chemical, optical, and electrical driving methods, magnetic driving has advantages such as deep penetration, flexible control, and relatively gentleness on biological tissues, making it particularly suitable for complex in vivo environments such as blood vessels, tumor stroma, mucosa, and soft tissues. However, most current research on magnetically driven microrobots mainly focuses on motion control in liquid environments or on planar hard substrates, such as tumbling, oscillation, rotational propulsion, and chain reconstruction driven by rotating magnetic fields. While these methods can achieve good visualization of motion in open liquid phases or ideal planes, they face significant challenges when microrobots enter actual biological tissue environments: First, real biological tissues are not simply liquid environments, but complex media that combine three-dimensional viscoelasticity, porous network structures, and local interfacial contact constraints, such as the extracellular matrix of tumor cells, collagen networks, and vascular endothelial layers. These environments can significantly alter the force state, posture evolution, and propulsion efficiency of microrobots.

[0003] Secondly, while traditional tumbling motion driven by rotating magnetic fields is simple in structure and easy to implement, it is often difficult to maintain an ideal pure rolling state in microscale interfaces. Due to factors such as insufficient contact, fluid lubrication, limited normal support, and interface disturbances, microrobots are prone to the coexistence of rolling and sliding during movement, resulting in significant speed loss, path dispersion, and limited penetration depth.

[0004] Third, for applications such as tumor tissue delivery, extravasation, and barrier crossing, mere movement in the liquid phase is insufficient. Microrobots need to further achieve directional, deep, and efficient active penetration in high-resistance, highly constrained tissue environments.

[0005] Therefore, there is an urgent need for a new magnetic field-driven control strategy to enable microrobots to maintain controllability in complex biological tissue environments while significantly enhancing propulsion efficiency and penetration capabilities. Summary of the Invention

[0006] The purpose of this application is to provide a method and system for controlling tissue penetration of magnetically responsive microrobots, which can enable magnetically responsive microrobots to propel themselves more stably and reduce slippage in complex biological environments, thereby achieving more efficient tissue penetration.

[0007] This application discloses a method for controlling tissue penetration by a magnetically responsive microrobot, including: S1. Place the magnetically responsive microrobot in the target biological environment to be penetrated; S2. Apply the main tumbling magnetic field to drive the magnetically responsive microrobot to tumble along the main tumbling plane; S3. Based on the main tumbling magnetic field, a periodic oscillating magnetic field component is superimposed along the third axis direction outside the main tumbling plane to form a three-dimensional wave magnetic field; S4. The magnetically responsive microrobot is driven by the three-dimensional wave magnetic field to generate attitude oscillations along the third axis during the tumbling motion, so as to modulate the normal contact state between the magnetically responsive microrobot and the target biological environment, increase the effective contact area and / or enhance frictional coupling, thereby suppressing slippage and realizing the penetrating movement of the magnetically responsive microrobot in the target biological environment.

[0008] In a preferred embodiment, the main tumbling magnetic field is a planar rotating magnetic field used to drive the magnetically responsive microrobot to tumble along the main tumbling plane.

[0009] In a preferred embodiment, a periodic oscillating magnetic field component is superimposed on the main tumbling magnetic field along a third axis direction perpendicular to the main tumbling plane.

[0010] In a preferred embodiment, the main tumbling plane is composed of magnetic field components in two intersecting directions.

[0011] In a preferred embodiment, the main tumbling plane is composed of a first direction magnetic field component and a second direction magnetic field component, and the third axis direction is different from the first direction and the second direction.

[0012] In a preferred embodiment, the primary tumbling plane is the xy plane, the xz plane, or the yz plane.

[0013] In a preferred embodiment, when the primary tumbling plane is the yz plane, the third axis direction is the x direction; when the primary tumbling plane is the xy plane, the third axis direction is the z direction; and when the primary tumbling plane is the xz plane, the third axis direction is the y direction.

[0014] In a preferred embodiment, the three-dimensional wave magnetic field is used to cause the magnetically responsive microrobot to transition from a state of coexistence of rolling and sliding to a rolling-dominant state during motion.

[0015] In a preferred embodiment, the periodic oscillating magnetic field component is used to cause the magnetically responsive microrobot to produce normal oscillations or wave-like attitude changes during tumbling propulsion.

[0016] In a preferred embodiment, the frequency of the periodic oscillating magnetic field component is adjusted according to the resistance characteristics of the target biological environment.

[0017] In a preferred embodiment, the main tumbling magnetic field and the periodic oscillating magnetic field component use the same frequency or different frequencies.

[0018] In a preferred embodiment, the frequency of the main tumbling magnetic field is 0 Hz-5 Hz.

[0019] In a preferred embodiment, a multi-frequency coupled three-dimensional wave magnetic field can be used to achieve graded propulsion at different depths or in different regions.

[0020] In a preferred embodiment, a tumbling motion mode is used when the environmental resistance of the target organism is low, and a wave motion mode is switched when the environmental resistance of the target organism increases.

[0021] In a preferred embodiment, the frequency of the periodic oscillating magnetic field component is 0 Hz to 10 Hz.

[0022] In a preferred embodiment, the magnetic field strength of the three-dimensional wave magnetic field is 0 mT-88 mT.

[0023] In a preferred embodiment, the magnetic field strength of the three-dimensional wave magnetic field is 74 mT.

[0024] In a preferred embodiment, the frequency of the three-dimensional wave magnetic field is 0 Hz-10 Hz.

[0025] In a preferred embodiment, the magnetically responsive microrobot is a single microrobot or a cluster of microrobots.

[0026] In a preferred embodiment, the magnetically responsive microrobot is a magnetic particle chain, magnetic capsule, magnetic helix, magnetic soft microstructure, or other microstructure capable of responding to external magnetic field drive.

[0027] In a preferred embodiment, the target biological environment is a collagen gel, extracellular matrix, vascular endothelial barrier, or tumor tissue.

[0028] In a preferred embodiment, the periodic oscillating magnetic field component is a sine wave, a square wave, a sawtooth wave, a pulse wave, a piecewise function waveform, or a combination thereof.

[0029] In a preferred embodiment, tissue penetration includes driving the magnetically responsive microrobot across the vascular endothelial barrier.

[0030] In a preferred embodiment, the tissue penetration includes active penetration of a magnetically responsive microrobot in a collagen gel.

[0031] In a preferred embodiment, the tissue penetration includes the directed migration of magnetically responsive microrobots in the extracellular matrix.

[0032] In a preferred embodiment, the tissue penetration includes deep penetration and intra-tissue extension of the magnetically responsive microrobot in tumor tissue.

[0033] In a preferred embodiment, during penetration, the tumbling motion mode, wave motion mode, and oscillating motion mode are dynamically switched according to tissue resistance.

[0034] This application also discloses a magnetically responsive microrobot tissue penetration control system, comprising: Main tumbling magnetic field generation module for generating the main tumbling magnetic field; Oscillating magnetic field generation module for generating the periodic oscillating magnetic field component of the third axis; A control module for controlling the superposition of the main rolling magnetic field and the periodic oscillating magnetic field components to form a three-dimensional wave magnetic field; The three-dimensional wave magnetic field is used to drive the magnetically responsive microrobot to penetrate tissues in the target biological environment.

[0035] In a preferred embodiment, the main tumbling magnetic field is generated by an array of permanent magnets.

[0036] In a preferred embodiment, the periodic oscillating magnetic field component in the third axis direction is generated by an electromagnetic coil.

[0037] In this embodiment, a periodic oscillating magnetic field with a third direction different from the main plane is introduced, enabling the microrobot to obtain additional normal oscillation or wave posture changes in addition to the original rolling motion. The resulting three-dimensional wave magnetic field is not a simple planar rotation, but a composite magnetic field with three-dimensional temporal control characteristics. This composite field maintains the overall forward rolling / propulsion trend on the one hand, and increases the dynamic contact area with the environment through third-axis oscillation on the other hand, improving friction conditions and thus enhancing tissue penetration ability.

[0038] Furthermore, by limiting the microrobot to produce normal oscillations or wave-like posture changes during tumbling propulsion, simple planar tumbling can be transformed into a composite motion state. In this way, the contact state between the microrobot and the target biological environment can be dynamically adjusted during the movement, thereby achieving more sufficient interface contact in key motion phases, improving friction conditions, reducing slippage losses, and making the driving force provided by the magnetic field more effectively converted into forward displacement. Therefore, it is more conducive to improving propulsion stability and tissue penetration ability.

[0039] The specification of this application contains numerous technical features distributed across various technical solutions. Listing all possible combinations of these technical features (i.e., technical solutions) would make the specification excessively lengthy. To avoid this problem, the various technical features disclosed in the above-described invention, the various technical features disclosed in the following embodiments and examples, and the various technical features disclosed in the accompanying drawings can be freely combined to form various new technical solutions (all of which are considered to have been described in this specification), unless such a combination of technical features is technically infeasible. For example, one example discloses feature A+B+C, and another example discloses feature A+B+D+E. Features C and D are equivalent technical means that serve the same function, and technically only one needs to be used; they cannot be used simultaneously. Feature E can technically be combined with feature C. Therefore, the solution A+B+C+D should not be considered as described because it is technically infeasible, while the solution A+B+C+E should be considered as described. Attached Figure Description

[0040] Figure 1 This is a schematic flowchart of a magnetically responsive microrobot tissue penetration control method according to one embodiment of this application.

[0041] Figure 2 This is a schematic diagram of a chain of microrobots performing a tumbling motion under an external magnetic field, according to one embodiment of this application.

[0042] Figure 3 This is a visualization of magnetic field superposition according to one embodiment of the present application, including in-plane tumbling magnetic fields ( B y + B z ) and out-of-plane three-dimensional wave magnetic field ( B y + B z + B x ).

[0043] Figure 4 This is a schematic diagram of a chain cluster of microrobots exhibiting tumbling and wave motions under the influence of an applied magnetic field, according to one embodiment of this application.

[0044] Figure 5 According to one embodiment of this application, a chain of microrobots performs tumbling and wave motions under the control of a magnetic field (8 mT, 0.5 Hz).

[0045] Figure 6This is a comparison of experimental and theoretical velocities of a chain swarm of microrobots under tumbling and wave motions according to one embodiment of this application.

[0046] Figure 7 This is a comparison of the contact area between a chain cluster of microrobots and a surface under wave motion and tumbling motion modes according to one embodiment of this application.

[0047] Figure 8 This is a comparison of the hybrid sliding-rolling speeds of a chain cluster of microrobots under wave motion and tumbling motion modes according to one embodiment of this application.

[0048] Figure 9 This is a comparison of the penetration distribution of collagen gel in a chain cluster of microrobots under wave motion and tumbling motion modes according to one embodiment of this application.

[0049] Figure 10 This is a comparison of the penetration distance of collagen gel in a chain cluster of microrobots under wave motion and tumbling motion modes according to one embodiment of this application.

[0050] Figure 11 This is an efficiency model of a microrobot chain cluster across the vascular endothelial barrier under wave motion mode according to one embodiment of this application.

[0051] Figure 12 According to one embodiment of this application, a microrobot chain cluster penetrates tumor tissue in a wave motion mode.

[0052] Figure 13 This is a schematic diagram of a magnetic response microrobot tissue penetration control system according to one embodiment of this application.

[0053] Figure 14 This is a schematic diagram of an integrated diagnostic and treatment solution using a magnetically responsive microrobot according to one embodiment of this application. Detailed Implementation

[0054] In the following description, many technical details are presented to help the reader better understand this application. However, those skilled in the art will understand that the technical solutions claimed in this application can be implemented even without these technical details and various variations and modifications based on the following embodiments.

[0055] the term To facilitate understanding of the technical solution of this application, some terms used herein are explained below, and this should not be construed as limiting the scope of protection of this application: (1) Main tumbling magnetic field: refers to the magnetic field used to drive the magnetic response microrobot to tumble along the main tumbling plane.

[0056] (2) Main tumbling plane: refers to the main motion plane formed by magnetic field components in two intersecting directions and used to form the tumbling drive.

[0057] (3) Three-dimensional wave magnetic field: refers to the three-dimensional composite magnetic field formed by superimposing the third axis periodic oscillating magnetic field component outside the main rolling plane on the main rolling plane magnetic field.

[0058] (4) Tumbling motion mode: refers to the motion mode in which the magnetic response microrobot undergoes periodic tumbling under the action of a planar rotating magnetic field and moves forward by relying on contact and friction with the interface.

[0059] (5) Wave motion mode: refers to the motion mode of magnetic response microrobots that, based on tumbling motion, produce normal oscillation or wave-like posture changes due to the effect of the periodic oscillating magnetic field component of the third axis, thereby enhancing contact and propulsion.

[0060] (6) Effective contact area: refers to the area of ​​the contact area where the magnetically responsive microrobot actually participates in frictional coupling with the surface of the tissue, gel or substrate at a certain moment.

[0061] (7) Slippage: refers to the phenomenon that the rotation of a magnetically responsive microrobot is not completely converted into rolling displacement without relative slippage during magnetic drive, resulting in relative interface slippage.

[0062] (8) Transendothelial transport: refers to the migration process of magnetically responsive microrobots from the vascular lumen side through the endothelial monolayer to the tissue side.

[0063] This application has at least the following advantages: Compared to traditional two-dimensional tumbling magnetic drives, this invention establishes a wave magnetic field with three-dimensional modulation capabilities by introducing a third-axis oscillation component outside the main tumbling plane. This method does not rely on increasing robot size or complicating robot structure; instead, it directly improves the contact mechanics between the robot and the interface by changing the spatiotemporal structure of the external field. Therefore, it has the advantages of simple implementation path, strong versatility, and easy scalability.

[0064] From a technical perspective, this invention can significantly suppress slippage during the tumbling process and improve the displacement per unit cycle and average propulsion speed. Especially in tissue simulation environments with high hardness and low porosity, its tissue penetration depth and migration speed are significantly better than traditional tumbling motion modes. At the same time, this method can also significantly enhance the active transport efficiency of microrobots across the endothelial barrier without significantly damaging the barrier integrity, thus making it more suitable for deep tissue delivery and in vivo targeted therapy scenarios.

[0065] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of this application will be described in further detail below with reference to the accompanying drawings.

[0066] This application relates to a method for controlling tissue penetration using a magnetically responsive microrobot, the process of which is as follows: Figure 1 As shown, it includes: In step S1, the magnetically responsive microrobot is placed in the target biological environment to be penetrated.

[0067] In step S2, a main tumbling magnetic field is applied to drive the magnetically responsive microrobot to tumble along the main tumbling plane.

[0068] In step S3, based on the main tumbling magnetic field, a periodic oscillating magnetic field component is superimposed along the third axis direction outside the main tumbling plane to form a three-dimensional wave magnetic field.

[0069] In step S4, the three-dimensional wave magnetic field is used to drive the magnetically responsive microrobot to generate attitude oscillations along the third axis during the tumbling motion, so as to modulate the normal contact state between the magnetically responsive microrobot and the target biological environment, increase the effective contact area and / or enhance the frictional coupling, thereby suppressing slippage and realizing the penetrating movement of the magnetically responsive microrobot in the target biological environment.

[0070] The mechanism of this invention is briefly explained below. The core of this mechanism is not simply "spinning faster," but rather altering the contact mechanics of the microrobot through a three-dimensional wave magnetic field. In traditional tumbling motion, the contact state between the robot and the interface changes periodically; when friction reserves are insufficient, slippage occurs, leading to losses during high-speed phases. This invention introduces normal modulation through third-axis oscillation, enabling the robot to obtain a larger effective contact area during critical motion phases, thereby achieving higher interfacial friction. Under microscale, low-load interfaces, friction primarily depends on the contact area, not just the normal load. With increased contact area, the system more easily meets the no-slip rolling condition, thus transforming the motion state from "rolling-slip coexistence" to "rolling-dominant," ultimately increasing the unit period displacement and average propulsion speed. In some embodiments, the primary tumbling magnetic field is a planar rotating magnetic field used to drive the magnetically responsive microrobot to tumble along the primary tumbling plane. Here, the primary tumbling magnetic field is a time-varying magnetic field constructed within a primary plane, causing the magnetically responsive microrobot to perform periodic posture flips within this plane and achieve forward tumbling propulsion through contact and friction with the interface. Compared to a static magnetic field or a single-axis oscillating magnetic field, this planar rotating magnetic field can continuously output the magnetic torque required for the microrobot to tumble, thereby providing the microrobot with a stable basic motion tendency.

[0071] Furthermore, the main tumbling plane can be formed by magnetic field components in two intersecting directions. B y and B zThe plane formed is taken as a preferred example, here B y , B z The directional notations used are merely based on a specific coordinate system and are intended to illustrate that the main tumbling magnetic field can be synthesized from two directional magnetic field components within the principal plane. They should not be construed as limiting this application to specific y- and z-directions. In other words, any planar rotating magnetic field capable of driving a magnetically responsive microrobot to tumble within the same principal plane can be considered the main tumbling magnetic field in this application. Therefore, the main tumbling plane can be the yz plane, the xy plane, the xz plane, or any other plane determined by two intersecting directions.

[0072] In some embodiments, a periodic oscillating magnetic field component is superimposed along a third axis direction perpendicular to the main tumbling plane, based on the main tumbling magnetic field. Here, the "third axis direction" refers to a direction different from the two directions constituting the main tumbling plane, used to introduce additional spatial orientation modulation outside the main tumbling plane. That is, when the main tumbling plane is composed of magnetic field components in the y and z directions, the third axis direction can be the x direction; when the main tumbling plane is composed of magnetic field components in the x and y directions, the third axis direction can be the z direction; and when the main tumbling plane is composed of magnetic field components in the x and z directions, the third axis direction can be the y direction. By superimposing a periodic oscillating magnetic field component along the third axis direction, the magnetically responsive microrobot can further generate planar normal oscillations or wave-like attitude changes on top of its original tumbling motion within the main plane, thereby forming a three-dimensional wave magnetic field with three-dimensional temporal modulation characteristics.

[0073] The periodic oscillating magnetic field component along the third axis works in conjunction with the main tumbling magnetic field. The main tumbling magnetic field maintains the overall forward tumbling propulsion tendency of the magnetically responsive microrobot, while the periodic oscillating magnetic field component along the third axis modulates the normal contact state between the magnetically responsive microrobot and the target biological environment. As a result, the magnetically responsive microrobot can achieve a more sufficient dynamic contact area and better frictional coupling conditions during movement, thereby reducing slippage losses and improving propulsion stability and tissue penetration capability.

[0074] To analyze the differences between the rolling and wave motion modes of the microrobot, this application establishes a motion mechanism model.

[0075] To analyze the motion behavior of a tumbling magnetic microrobot ( Figure 2 This application defines the model as a cross-sectional view of the robot in the yz plane: in, and Let f represent the magnetic force along the y and z directions, respectively; f represents the frictional force obtained from the rotational dynamics equation; I is the moment of inertia; R is the contact radius; and θ is the angle between the chain and the surface. and These represent the force and torque generated by the dipole interaction, respectively; N is the normal force, and L is the buoyancy force acting on the microrobot.

[0076] In an ideal tumbling motion, a microrobot could travel approximately two of its own length per cycle. However, in experiments, the microrobot's speed was far below its theoretical maximum. This phenomenon indicates that tumbling and sliding coexist: during tumbling, friction is insufficient to support the microrobot's pure rolling for most of the time. Furthermore, the traditional law of friction, that "friction force is proportional to normal force," does not apply here; instead, the contact area plays a more crucial role, with a larger contact area resulting in a more significant increase in friction.

[0077] Within the contact region, the surface morphology can be approximated by a second-order Taylor expansion as follows: The local effective radius of curvature is given by the following formula: Since the curvature changes with the rotation angle, its variation is modeled using a cosine function. Let... It is the effective radius of curvature (i.e., the minimum local curvature) when the thicker middle part of the object comes into contact with the surface. Let be the effective radius of curvature (i.e., the local maximum curvature) when the sharper end contacts the surface. Based on this, a simple periodic model can be used as follows: Where ω is the angular velocity and t is time. According to Hertzian contact theory, when a sphere (or a surface that is locally approximated as a sphere) presses onto a plane, the contact area can be considered as a circle, and its contact circle radius a is: Where F is the applied normal load, The effective (or composite) elastic modulus of the contact material is determined by... Given: The contact area during tumbling is: Additional oscillations introduce additional periodic regions, and the contact area in the wave motion pattern is: Substitute the parameters into the function, where 𝑎=2×10 -5 m, 𝑏=2×10 -6m, elastic modulus E = 50 MPa, Poisson's ratio ν = 0.4. For example... Figure 7 As shown, the swaying motion mode has a larger contact area compared to the tumbling motion mode.

[0078] For low-load interfaces at the microscale, friction can be expressed as: During group tumbling, interfacial shear strength The change is small and can be considered constant. Therefore, the friction force mainly depends on the contact area. In other words, the sliding behavior indicates that the contact area is insufficient to make the microrobot roll.

[0079] For any convex body, its support function h(n) can be defined as the distance from the centroid to the support line perpendicular to the unit vector 𝑛. Since the ellipse is rotated by an angle relative to the world coordinate system, the outward (upward) normal of the ellipse at the point of contact is obtained by "rotating" the perpendicular line. In the ellipse's body coordinate system, the support line distance (support function) in this direction is given by: Parameters 𝑎 and 𝑏 are semi-axes; generally, if the ellipse is "flattened" in the vertical direction, the vertical semi-axis should be smaller than 𝑎. Therefore, the horizontal displacement of the center during a small rotation is given by the following x-components: Therefore, the instantaneous horizontal (x-direction) velocity of the center of mass is: If denoted as ,So Given that 𝑎> 𝑏, therefore Take the maximum value: Take the minimum value: .

[0080] In summary, the above formulas collectively demonstrate that by introducing a third-axis periodic oscillation on the basis of the main tumbling magnetic field, this application enables the microrobot to obtain a larger dynamic contact area and better friction conditions, thereby reducing slippage loss, improving propulsion efficiency, and ultimately enhancing its tissue penetration ability in complex biological environments.

[0081] In some embodiments, a three-dimensional wave magnetic field can be generated by a wave motion magnetic field device. Figure 13The wave motion magnetic field device may include electromagnetic coils and a permanent magnet array. The electromagnetic coils generate a periodic oscillating magnetic field, and the permanent magnet array generates a tumbling motion mode magnetic field through axial rotation. In this embodiment, a rotating magnetic field is first established on the main tumbling plane, and then a periodic oscillating component is superimposed along the third axis to form a three-dimensional wave magnetic field. Figure 3 Preferably, the main tumbling plane is... B y + B z The third axis oscillation component in the plane is B x directional oscillating magnetic field, thus forming B y + B z + B x A three-dimensional wave magnetic field. This three-dimensional wave magnetic field is not a simple two-dimensional rotation, but rather introduces spatial outward normal modulation while maintaining the main tumbling motion trend, enabling the microrobot to produce more obvious posture changes and interface contact reconstruction within a driving cycle. Figure 4 Compared to using only in-plane tumbling magnetic fields, this three-dimensional wave magnetic field can significantly enhance the effective contact area of ​​microrobots during motion and improve frictional coupling capabilities.

[0082] To address the issue of slippage dominance and limited propulsion efficiency in tumbling motion, this application introduces a key modification to the driving strategy: superimposing an oscillating component along a third axis outside the main rotation plane. This results in more pronounced normal modulation of the microrobot during periodic motion, thereby increasing the effective contact area and enhancing frictional interaction. In this embodiment, the microrobots move in a chain-like cluster. The following analysis compares and contrasts the cluster motion behavior in tumbling and wave motion modes. In wave motion mode, the microrobots advance approximately 0.63 body lengths per cycle. Figure 5 In the tumbling motion mode, the forward displacement per cycle is approximately 0.27 body lengths ( Figure 6 The above results indicate that the third-axis oscillation component can be improved by increasing the contact area and enhancing frictional coupling. Figure 7 ), effectively suppressing slippage and improving rolling propulsion efficiency ( Figure 8 ).

[0083] In addition to the above-described embodiments, the three-dimensional wave magnetic field driving method of this application can also achieve tissue penetration control using the following alternative solutions. It should be noted that the following alternative solutions can be implemented individually or in any combination, without departing from the technical concept of this application.

[0084] In some embodiments, the tumbling, wave, and oscillating motion modes can be dynamically switched during tissue penetration based on changes in resistance in the target biological environment. For example, in the tissue surface or relatively loosely structured areas with low local resistance, large pores, and a high proportion of fluid environment, the tumbling motion mode is preferred. In this mode, the microrobot advances by periodically tumbling around its short or long axis driven by a rotating magnetic field, suitable for rapid propulsion and initial entry in low-resistance environments. For example, in necrotic areas at tumor margins, loose matrix areas, or low-density collagen networks, the tumbling mode can be maintained to achieve greater displacement efficiency when the movement speed is high and the posture disturbance is small.

[0085] As the microrobot continues to penetrate deeper into the tissue, entering regions with denser fiber arrangement, narrower pores, and increased viscoelastic resistance, it can switch to a wave-like motion mode. In this mode, by periodically changing the direction or phase of the magnetic field, the microrobot generates continuous wave-like propulsion, thereby reducing direct confrontation with the surrounding matrix and enhancing its adaptability to complex channels and non-uniform interfaces. This mode is particularly suitable for areas with interwoven collagen fibers, dense matrix areas, or areas with tortuous microchannels. For example, when a significant decrease in forward speed, an increase in slip ratio, or localized instability is detected in the tumbling mode, the system can switch to wave mode to improve its sustained penetration capability into high-resistance tissues.

[0086] When the microrobot reaches areas of extremely high local resistance, fiber entanglement, or narrow jamming sites, or when local perturbation, in-situ release, or dwelling is required near the target area, it can be further switched to an oscillating motion mode. In this mode, an alternating or reciprocating magnetic field is applied, causing the microrobot to perform small-amplitude, high-frequency oscillations or reciprocating vibrations locally. This reduces static friction and local adhesion, promotes loosening, rearrangement, or local softening of the surrounding matrix, and helps the microrobot overcome its jamming state. This mode is suitable for penetrating ends, locally blocked areas, and situations requiring enhanced release of local therapeutic molecules and tissue interaction. For example, when the microrobot cannot effectively move forward in wave mode, or when the displacement per unit time is below a preset threshold, it can be switched to oscillating mode for local unblocking or in-situ action.

[0087] In some embodiments, a multi-frequency coupled three-dimensional wave magnetic field can be used to achieve graded propulsion at different depths or in different regions. Specifically, different frequencies can be applied to the main tumbling magnetic field and / or the periodic oscillating magnetic field component in the third axis direction, or different frequency combinations can be switched at different penetration stages to adapt to the mechanical properties and resistance distribution of different tissue regions. For example, in one embodiment, a frequency combination of low-frequency main tumbling and high-frequency third-axis micro-oscillation can be used. Specifically, the frequency of the main tumbling magnetic field can be set to 1~3 Hz, and the frequency of the third-axis oscillating magnetic field can be set to 8~10 Hz. This combination is suitable for the penetration stage from the surface to the middle and shallow layers of tissue, where the main tumbling magnetic field is used to provide stable overall propulsion, and the high-frequency micro-oscillation of the third axis is used to continuously weaken local adhesion, reduce interfacial static friction, and promote the loosening of the surrounding matrix. This method is particularly suitable for regions where the pore structure is not completely closed, but there is already some fiber binding and viscoelastic resistance.

[0088] In another embodiment, a frequency combination of mid-frequency main tumbling and low-frequency third-axis oscillation can be used. Specifically, the main tumbling magnetic field frequency can be set to 3~6 Hz, and the third-axis oscillating magnetic field frequency can be set to 0.5~2 Hz. This combination is suitable for tissue regions with directional fiber arrangements or wavy channel structures. The main tumbling provides continuous propulsion, while the low-frequency third-axis oscillation can periodically change the contact direction between the microrobot and the fiber network, making it easier to deflect and redirect along local weak resistance directions, thereby improving channel adaptability in anisotropic tissues.

[0089] In another embodiment, a dual low-frequency combination of low-frequency main tumbling and low-frequency third-axis oscillation can be employed. Specifically, the frequency of the main tumbling magnetic field can be set to 1-2 Hz, and the frequency of the third-axis oscillation magnetic field can be set to 1-3 Hz, with a fixed phase difference between the two, such as 90° or 180°. This combination can form a relatively gentle spiral wave trajectory in three-dimensional space, suitable for deep tissue regions with high viscosity and low porosity but not yet completely blocked. Compared with a single tumbling mode, this approach can reduce frontal compression with the surrounding matrix and enhance barrier avoidance and slow-release propulsion capabilities.

[0090] In another embodiment, a combination of high-frequency main tumbling and intermittent low-frequency pulse oscillations on the third axis can be used. Specifically, the frequency of the main tumbling magnetic field can be set to 5~10 Hz, and the third-axis oscillating magnetic field is applied discontinuously, with its pulse frequency set to be inserted once every 2~10 tumbling cycles, and each pulse lasting 0.1~1 s. This embodiment is suitable for situations requiring rapid passage through relatively loose regions, but occasionally encountering localized dense nodes or short-range jamming. The main tumbling is used to maintain high propulsion efficiency, and the third-axis pulse disturbance is used to instantaneously release localized jamming or disrupt temporarily formed adhesive interfaces when encountering obstacles.

[0091] In some embodiments, the three-dimensional wave magnetic field can also be coupled with functions such as drug release, temperature control, ultrasound imaging, or photoacoustic localization to form an integrated diagnostic and therapeutic solution, such as... Figure 14 As shown.

[0092] For example, in one specific embodiment, a magnetically controlled microrobot is introduced into the tumor region via intratumoral injection, peritumoral injection, or intravenous administration followed by tumor enrichment. Subsequently, a three-dimensional wave magnetic field is applied to spatially drive the microrobot. The three-dimensional wave magnetic field may include a main tumbling magnetic field component and a third-axis oscillating magnetic field component, wherein the main tumbling magnetic field is used to drive the microrobot forward along the tumor interior, and the third-axis oscillating magnetic field is used to reduce local adhesion and enhance the ability to disturb dense matrix regions, thereby improving its penetration depth and distribution uniformity in tumor tissue.

[0093] In some implementations, the three-dimensional wave magnetic field can also be superimposed with an alternating magnetic field heating function, or a time-sequential switching method can be used between the driving and heating phases. Specifically, after the microrobot penetrates to the target area, an alternating magnetic field of preset frequency and intensity is applied, causing the magnetic particles attached to the surface of the microrobot to undergo a magnetocaloric effect, resulting in a local temperature increase around the microrobot. This can trigger a temperature-sensitive treatment module, promoting local drug release or enhancing the therapeutic response of the lesion tissue. The local therapeutic response can manifest as changes in the mechanical properties of the lesion tissue, weakening of the local barrier, or increased tissue permeability. Thus, the deep enrichment achieved by the three-dimensional wave magnetic field can further enhance the local therapeutic effect; while the reduced tissue resistance caused by the local therapeutic effect is conducive to the three-dimensional wave magnetic field continuing to drive the magnetically responsive therapeutic carrier to penetrate deeper into the region, thereby forming a synergistic effect between enhanced penetration and enhanced local treatment.

[0094] In other embodiments, a clinical ultrasound shear wave elastography system and a magnetic resonance imaging (MRI) system can be used to monitor the above process in real time. The ultrasound shear wave elastography system is used to acquire changes in the elastic modulus of the lesion tissue before, during, and after treatment to evaluate the dynamic changes in the mechanical properties of the lesion tissue. The MRI system is used to utilize the imaging contrast characteristics of magnetic particles to monitor the spatial distribution, migration path, and accumulation areas of the magnetically controlled microrobot within the lesion tissue in real time. By jointly analyzing the lesion tissue stiffness distribution information obtained from ultrasound shear wave elastography and the microrobot distribution information obtained from MRI, a dynamic correspondence of "robot distribution—local softening—further penetration" can be established, thereby providing imaging evidence for the adjustment of three-dimensional wave magnetic field parameters.

[0095] For example, in a specific treatment procedure, magnetic resonance imaging can be used first to determine the initial boundary of the lesion tissue and the initial distribution after the microrobot injection; then, a first-stage three-dimensional wave magnetic field is applied to advance the microrobot into the superficial and middle layers of the lesion tissue; after reaching the predetermined enrichment level, a second-stage magnetothermal trigger magnetic field is applied to induce the expression of temperature-sensitive treatment modules; then, ultrasonic shear wave elastography is used to detect whether the local stiffness of the lesion tissue has decreased, and the direction, frequency, or amplitude of the three-dimensional wave magnetic field is readjusted according to the area of ​​decreased stiffness, so that the microrobot can further penetrate into the high-stiffness residual area; this process is repeated until the target lesion tissue area achieves the expected effect and the microrobot reaches the expected distribution depth.

[0096] The second embodiment of this application relates to a magnetically responsive microrobot tissue penetration control system, comprising: Main tumbling magnetic field generation module for generating the main tumbling magnetic field; Oscillating magnetic field generation module for generating the third-axis periodic oscillating magnetic field component; A control module for controlling the superposition of the main rolling magnetic field and the periodic oscillating magnetic field components to form a three-dimensional wave magnetic field; The three-dimensional wave magnetic field is used to drive the magnetically responsive microrobot to penetrate tissues in the target biological environment.

[0097] In some embodiments, the main tumbling magnetic field generation module can be implemented by a permanent magnet array, which generates a tumbling motion mode magnetic field by axial rotation; the oscillating magnetic field generation module can be implemented by an electromagnetic coil, which is used to generate a periodic oscillating magnetic field component in the third axis direction; and the control module is used to coordinate the timing, direction and superposition relationship between the main tumbling magnetic field and the periodic oscillating magnetic field component to form a three-dimensional wave magnetic field.

[0098] like Figure 13 As shown, this application presents a wave motion magnetic field device composed of a permanent magnet ring array (gray block) and a coaxial electromagnetic coil (red spiral). The permanent magnet rotates at a constant speed with the motor to generate a rotating magnetic field with continuously changing direction, and the electromagnetic coil is superimposed with an alternating current to synchronously output an axial oscillating magnetic field.

[0099] To further verify the application effect of the magnetic response microrobot tissue penetration control method of this application in complex biological environments, the performance of the method in three-dimensional viscoelastic matrix penetration, transvascular endothelial barrier transport, and tumor tissue penetration is described below in conjunction with in vitro and in vivo experiments. It should be noted that the following experimental examples are mainly used to verify the technical effects of the method of this application and do not constitute a limitation on the scope of protection of this application.

[0100] In vitro evaluation of penetration effect in three-dimensional viscoelastic matrix To verify the penetration ability of this invention in a simulated tissue environment, collagen gel models with different mechanical properties were established in this embodiment. Collagen solutions were prepared using rat tail type I collagen stock solution, sterile double-distilled water, PBS buffer, and 1 M NaOH, adjusting the final collagen concentration to 2.5 mg / mL. The pH of the collagen solutions was adjusted to 7.5, 9.5, and 11.5, respectively, and added to one side of a coverslip with a cavity, making its volume approximately one-third of the entire cavity volume. Gel polymerization was then completed by incubation at 37°C and 5% CO2 for 30 minutes. After polymerization, the gel was thoroughly rinsed with PBS, and the remaining space was filled with culture medium.

[0101] After cross-linking was completed on one side of the collagen gel, microrobots were placed at the end of the liquid phase. A rotating magnetic field was first applied to drive them to form dense clusters, with the preferred pre-assembly parameters being 260 mT, 2 Hz, and 10 minutes. Then, a wave motion mode or a tumbling motion mode was switched to drive the microrobots to penetrate the collagen gel, with the preferred magnetic field parameters for the penetration stage being 78 mT and 60 minutes. The distribution and penetration depth of the microrobots within the gel were imaged and analyzed using a laser scanning confocal microscope. A control group without a magnetic field was also included. The experimental results showed that, regardless of whether it was the tumbling or wave motion mode, the penetration depth of the microrobot clusters in gels of different hardness increased with increasing magnetic field frequency, reaching a maximum at 5 Hz; however, there were significant differences in penetration ability between the two modes. Furthermore, the wave motion mode exhibited a more concentrated and directional migration trajectory, while the tumbling motion mode showed a more dispersed spatial distribution. Figure 9 and Figure 10 ).

[0102] In vitro evaluation of the transvascular endothelial barrier transport efficiency of microrobots under wave motion mode After verifying that the present invention can significantly improve the active penetration ability in a three-dimensional viscoelastic matrix, its applicability in biological barrier crossing scenarios was further investigated. Microrobots were added to the upper chamber of a Transwell and driven to cross the endothelial monolayer under the action of a three-dimensional wave magnetic field. The amount of microrobots in the lower chamber was measured after 1 hour. Preferably, the three-dimensional wave magnetic field parameters were 74 mT, 2 Hz, and 1 hour. The results showed that without an external magnetic field, the passive diffusion of the microrobots after 1 hour was only about 0.88%; after applying the three-dimensional wave magnetic field, the transendothelial transport was increased by approximately 26.25 times compared to passive diffusion. Figure 11 Further comparison revealed that the lower frequency group could achieve higher transport volume under certain conditions, indicating that the driving frequency not only affects propulsion kinematics but also the efficiency of interaction with the endothelial interface.

[0103] In vivo assessment of the tumor penetration effect of the microrobot in wave motion mode To evaluate the penetration effect of wave motion pattern on tumor tissue in tumor-bearing mice, a subcutaneous 4T1 breast cancer tumor mouse model was established. Wave motion pattern actuation began after injection of the microrobots, with WMF (74 mT, 5 Hz) driving for 60 minutes daily for 3 consecutive days. Magnetic resonance imaging (MRI) was used to record the distribution of the microrobots in tumor tissue on day 7, comprehensively evaluating the penetration effect of the microrobot cluster on tumor tissue under wave motion pattern. Comparison of MRI scans before injection and on day 7 after treatment clearly showed the migration and distribution depth of the microrobots within the tumor, indicating that the advancement of wave motion pattern can significantly enhance deep penetration and intra-tissue expansion in vivo. Figure 12 ).

[0104] It should be noted that in this patent application, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one" does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element. In this patent application, if it refers to performing an action according to an element, it means performing the action at least according to that element, including two cases: performing the action only according to that element, and performing the action according to that element and other elements. Expressions such as "multiple," "repeatedly," and "various" include two, two times, two kinds, and more than two, more than two times, and more than two kinds.

[0105] The numbering used in describing the steps of a method does not inherently limit the order of these steps. For example, a step with a higher number does not necessarily have to be executed after a step with a lower number; it can be executed first and then second, or even in parallel, as long as this execution order is reasonable to someone skilled in the art. Similarly, multiple steps with consecutively numbered sequences (e.g., step 101, step 102, step 103, etc.) do not restrict other steps from being executed between them; for example, there can be other steps between step 101 and step 102.

[0106] All documents mentioned in this application are considered to be incorporated in their entirety into the disclosure of this application so that they can serve as a basis for modifications if necessary. Furthermore, it should be understood that after reading the foregoing disclosure of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the scope of protection claimed in this application.

Claims

1. A method for controlling tissue penetration using a magnetically responsive microrobot, characterized in that, include: S1. Place the magnetically responsive microrobot in the target biological environment to be penetrated; S2. Apply the main tumbling magnetic field to drive the magnetically responsive microrobot to tumble along the main tumbling plane; S3. Based on the main tumbling magnetic field, a periodic oscillating magnetic field component is superimposed along the third axis direction outside the main tumbling plane to form a three-dimensional wave magnetic field; S4. The magnetically responsive microrobot is driven by the three-dimensional wave magnetic field to generate attitude oscillations along the third axis during the tumbling motion, so as to modulate the normal contact state between the magnetically responsive microrobot and the target biological environment, increase the effective contact area and / or enhance frictional coupling, thereby suppressing slippage and realizing the penetrating movement of the magnetically responsive microrobot in the target biological environment.

2. The tissue penetration control method for magnetically responsive microrobots as described in claim 1, characterized in that, The main tumbling magnetic field is a planar rotating magnetic field used to drive the magnetically responsive microrobot to tumble along the main tumbling plane.

3. The tissue penetration control method for magnetically responsive microrobots as described in claim 1, characterized in that, Based on the main tumbling magnetic field, a periodic oscillating magnetic field component is superimposed along a third axis direction perpendicular to the main tumbling plane.

4. The tissue penetration control method for magnetically responsive microrobots as described in claim 1, characterized in that, The main tumbling plane is composed of magnetic field components in two intersecting directions.

5. The magnetic response microrobot tissue penetration control method as described in claim 1, characterized in that, The main tumbling plane is composed of a first direction magnetic field component and a second direction magnetic field component, and the third axis direction is different from the first direction and the second direction.

6. The tissue penetration control method for magnetically responsive microrobots as described in claim 1, characterized in that, The periodic oscillating magnetic field component is used to cause the magnetically responsive microrobot to produce normal oscillations or wave-like attitude changes during tumbling propulsion.

7. The tissue penetration control method for magnetically responsive microrobots as described in claim 1, characterized in that, The magnetically responsive microrobot is a single microrobot or a cluster of microrobots.

8. The tissue penetration control method for magnetically responsive microrobots as described in claim 1, characterized in that, The target biological environment is collagen gel, extracellular matrix, vascular endothelial barrier or tumor tissue.

9. The tissue penetration control method for magnetically responsive microrobots as described in claim 1, characterized in that, The periodic oscillating magnetic field component is a sine wave, square wave, sawtooth wave, pulse wave, piecewise function waveform, or a combination thereof.

10. A magnetically responsive microrobot tissue penetration control system, characterized in that, include: Main tumbling magnetic field generation module for generating the main tumbling magnetic field; Oscillating magnetic field generation module for generating the periodic oscillating magnetic field component of the third axis; A control module for controlling the superposition of the main rolling magnetic field and the periodic oscillating magnetic field components to form a three-dimensional wave magnetic field; The three-dimensional wave magnetic field is used to drive the magnetically responsive microrobot to penetrate tissues in the target biological environment.

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