Deep-lung targeted delivery method, and micro-robot swarm

Abstract

Disclosed in the present invention are a deep-lung targeted delivery method, and a micro-robot swarm. The method comprises: preparing microgel particles including magnetic microparticles, imaging particles and cargo, and combining the prepared microgel particles to obtain a micro-robot swarm; controlling the movement, climbing and reconstruction of the micro-robot swarm in a non-fluid environment, so as to realize movement within a porous duct environment; and controlling the micro-robot swarm to move in a lung sample under the guidance of X-rays, and delivering the micro-robot swarm to a target bronchus in the lung sample; or controlling the micro-robot swarm to perform delivery in a target lung under the guidance of computed tomography imaging, and to release encapsulated cargo at a target bronchus. The micro-robot swarm provided by the present invention can realize targeted delivery in an air-filled lung environment, a lung environment with a mucus layer, and a deep-lung target bronchus.

Description

A lung deep layer targeted delivery method and micro robot cluster TECHNICAL FIELD

[0001] The present application relates to the technical field of micro-nano robots, and particularly relates to a lung deep layer targeted delivery method and micro robot cluster. BACKGROUND

[0002] Pulmonary delivery of therapeutic drugs has become a focus for treating various lung diseases, such as lung cancer, cystic fibrosis and pneumonia. Although systemic administration routes such as oral and intravenous injection can effectively deliver drugs to the lung through blood circulation, it often leads to drug accumulation and toxicity in non-target sites. The inhalation route can bypass the first-pass metabolism of the liver, helping the drug to exert its effect in the lung, but it faces the problem of non-selective distribution of inhaled drugs in the lung, which brings adverse effects to healthy tissues. In order to achieve precise local drug delivery in the lung, bronchoscopes have been used for drug instillation or direct injection to deliver drugs to the location close to the target lesion. However, the movement flexibility of the traditional bronchoscope is limited, and it is difficult to adapt to the tortuous and narrow bronchial tree in the lung. Therefore, it is necessary to develop new technologies to precisely deliver drugs to the target lesion site in the lung.

[0003] Active micro robot clusters provide a promising solution to deliver therapeutic drugs to hard-to-reach lesion sites in the human body. Micro robot clusters have the ability of remote controllability, movement flexibility and enhanced medical imaging contrast, and have been proven to be useful for the delivery of therapeutic drugs. Magnetic micro robot clusters have achieved targeted delivery in different physiological environments such as knee joints, eyes and blood vessels. Through gradient magnetic field driving, magnetic micro scaffold clusters have successfully delivered stem cells to the cartilage defect site of the rabbit knee joint. In the vitreous body of the pig eye, a cluster composed of smooth spiral nanorobots has been driven to the retina. Under the guidance of X-ray, magnetic particle clusters have shown the ability to reach the target area in the liver of rats and the kidney of pigs. However, due to factors such as the non-fluid environment of the lung, the mucus layer and the irregular bronchial tree structure, active micro robot clusters face major challenges in targeted delivery in the lung.

[0004] Therefore, the prior art still needs to be improved. SUMMARY

[0005] The technical problem solved by the present application is that, in view of the defects in the prior art, the present application provides a lung deep layer targeted delivery method and micro robot cluster to solve the problem that the existing micro robot cluster cannot accurately target drug delivery in the lung gas environment.

[0006] The technical solution adopted by the present application to solve the technical problem is as follows:

[0007] In a first aspect, the present application provides a method for deep lung targeted delivery, comprising:

[0008] Preparation of microgel particles containing magnetic microparticles, developing particles and cargos, and combination of the prepared microgel particles to obtain a micro-robot cluster;

[0009] Controlling the motion, climbing and reconfiguration of the micro-robot cluster in a non-fluid environment to realize motion in a porous pipe environment;

[0010] Controlling the motion of the micro-robot cluster in the lung sample under the guidance of X-ray, delivering the micro-robot cluster to the target bronchus of the lung sample; or controlling the delivery of the micro-robot cluster in the target lung under the guidance of computed tomography imaging, and releasing the wrapped cargo in the target bronchus.

[0011] In an implementation, the controlling the motion, climbing and reconfiguration of the micro-robot cluster in a non-fluid environment to realize motion in a porous pipe environment comprises:

[0012] Placing the micro-robot cluster on a platform above a permanent magnet;

[0013] Controlling the rotating and translating motion of the permanent magnet to change the magnitude and direction of the gradient force applied to the micro-robot cluster, so that the micro-robot cluster follows the translating motion of the permanent magnet;

[0014] When the micro-robot cluster moves in the pipe structure, slowly move the rotating permanent magnet around the outer surface of the pipe to make the micro-robot cluster climb the wall surface;

[0015] Adjusting the angle of the permanent magnet and performing oscillation motion to make the particles in the micro-robot cluster gather in the vertical direction, and convert the shape of the micro-robot cluster into a columnar structure;

[0016] When the micro-robot cluster is in the columnar structure, control the motion of the micro-robot cluster in the porous pipe environment by slowly moving the permanent magnet.

[0017] In an implementation, the adjusting the angle of the permanent magnet and performing oscillation motion to make the particles in the micro-robot cluster gather in the vertical direction, and convert the shape of the micro-robot cluster into a columnar structure comprises:

[0018] Adjusting the angle of the permanent magnet to make the magnetization axis of the permanent magnet perpendicular to the plane where the micro-robot cluster is located, and performing oscillation motion to convert the micro-robot cluster from a planar structure to a columnar structure, and reduce the coverage area of the micro-robot cluster.

[0019] In an implementation, the controlling the swarm of microrobots to move in the lung sample under the guidance of X-ray includes:

[0020] Placing the lung sample under an X-ray imaging device;

[0021] Observing the bronchial distribution of the lung sample using X-ray imaging to determine a delivery path and a permanent magnet driving mode;

[0022] Filling the swarm of microrobots into a catheter and placing the catheter into a bronchoscope lumen to deploy the swarm of microrobots to a main bronchus;

[0023] Removing the bronchoscope, applying a rotating permanent magnet, and slowly moving the permanent magnet along the predetermined path to guide the swarm of microrobots to move;

[0024] According to a target bronchus type of the lung sample, guiding the swarm of microrobots to move from beside an entrance of a downward bronchus or moving the swarm of microrobots from a bottom surface to a top surface until moving to the target bronchus.

[0025] In an implementation, the guiding the swarm of microrobots to move from beside the entrance of the downward bronchus includes:

[0026] When encountering the downward bronchus, switching the permanent magnet driving mode to a shaking mode, changing a shape of the swarm of microrobots to reduce a swarm coverage area, and guiding the swarm of microrobots to move from beside the entrance of the downward bronchus.

[0027] In an implementation, the moving the swarm of microrobots from the bottom surface to the top surface until moving to the target bronchus includes:

[0028] When an upward inclined bronchus is the target bronchus, placing the rotating permanent magnet above the swarm of microrobots to move the swarm of microrobots from the bottom surface to the top surface until moving to the target bronchus.

[0029] In an implementation, the controlling the swarm of microrobots to move in the lung sample under the guidance of X-ray includes:

[0030] Scanning the target lung using a computed tomography scanner and performing bronchial three-dimensional structure reconstruction and delivery path planning;

[0031] Orally placing a tracheal tube to a lung trachea and inserting a bronchoscope to a main bronchus through the tracheal tube;

[0032] filling the micro-robot cluster into a catheter, inserting the catheter into a bronchoscope lumen, and delivering the micro-robot cluster to a main bronchus of the target lung;

[0033] applying and moving the permanent magnet to guide the motion of the micro-robot cluster, and using the computed tomography to determine the position of the micro-robot cluster in the moving gap, adjusting the position and angle of the permanent magnet;

[0034] adjusting the driving mode of the permanent magnet according to the position of the micro-robot cluster, and controlling the micro-robot cluster to release the wrapped cargo in the target bronchus.

[0035] In an implementation manner, the adjusting the driving mode of the permanent magnet according to the position of the micro-robot cluster, and controlling the micro-robot cluster to release the wrapped cargo in the target bronchus comprises:

[0036] when encountering a downward bronchus, making the permanent magnet perform a shaking motion to change the shape of the micro-robot cluster and reduce the coverage area, and guiding the micro-robot cluster to pass through the downward bronchus;

[0037] when the micro-robot cluster reaches a deep target bronchus, using the permanent magnet to fix the micro-robot cluster in the target bronchus, and releasing the wrapped cargo.

[0038] In a second aspect, the present application provides a micro-robot cluster for implementing the lung deep targeted delivery method of the first aspect, and the micro-robot cluster comprises:

[0039] The micro-robot cluster comprises magnetic particles, developing particles and microgel particles of cargo; the micro-robot cluster is used for motion, climbing and reconstruction in a non-fluid environment, motion in a pipe environment with holes, motion in a lung sample under the guidance of X-ray, delivery of cargo to a target bronchus of the lung sample, or delivery in a target lung under the guidance of computed tomography imaging, and release of the wrapped cargo in the target bronchus.

[0040] The present application has the following effects by adopting the above technical solutions:

[0041] The present application can obtain a micro-robot cluster by preparing micro-gel particles containing magnetic particles, developing particles and cargos, and combining the prepared micro-gel particles; and can realize movement in a porous pipe environment by controlling the movement, climbing and reconstruction of the micro-robot cluster in a non-fluid environment; and can deliver the micro-robot cluster to a target bronchus of a lung sample by controlling the movement of the micro-robot cluster in the lung sample under the guidance of X-ray; or control the delivery of the micro-robot cluster in a target lung under the guidance of computer tomography imaging, and release the wrapped cargos in the target bronchus; the micro-robot cluster provided by the present application can realize the targeted delivery in an air-filled lung environment, a lung environment with a mucus layer and a deep lung target bronchus. BRIEF DESCRIPTION OF DRAWINGS

[0042] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or prior art description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor based on the drawings shown.

[0043] Fig. 1 is a flow chart of a deep lung targeted delivery method in the preferred embodiment of the present application.

[0044] Fig. 2 is a schematic diagram of the composition of magnetic micro-gel particles in the preferred embodiment of the present application.

[0045] Fig. 3(a) is a schematic diagram of the generation of a micro-robot cluster in the preferred embodiment of the present application; and Fig. 3(b) is a schematic diagram of the movement of a micro-robot cluster in the preferred embodiment of the present application.

[0046] Fig. 4(a) is a schematic diagram of the shape reconstruction of a micro-robot cluster in the preferred embodiment of the present application; and Fig. 4(b) is a schematic diagram of the movement of a micro-robot cluster in a porous pipe environment in the preferred embodiment of the present application.

[0047] Fig. 5 is a schematic diagram of the delivery of a micro-robot cluster in an ex vivo pig lung under the guidance of X-ray imaging in the preferred embodiment of the present application.

[0048] Fig. 6 is a schematic diagram of the delivery of a micro-robot cluster in a target pig lung under the guidance of computer tomography imaging in the preferred embodiment of the present application.

[0049] The purposes, functional features and advantages of the present application will be further described with reference to the embodiments and the accompanying drawings. DETAILED DESCRIPTION

[0050] In order to make the objects, technical solutions and advantages of the present application clearer and more apparent, the present application will be further described in detail below with reference to the drawings and examples. It should be understood that the specific examples described herein are only used to explain the present application and not to limit the present application.

[0051] Exemplary method

[0052] Active microrobotic swarms provide a promising solution to deliver therapeutic drugs to hard-to-reach diseased sites in the human body. Microrobotic swarms have the ability of remote controllability, motion flexibility, and enhanced medical imaging contrast, and have been proven to be useful for the delivery of therapeutic drugs. Magnetic microrobotic swarms have achieved targeted delivery in different physiological environments such as knee joints, eyes, and blood vessels. Through gradient magnetic field driving, magnetic microscaffold swarms have successfully delivered stem cells to the cartilage defect site of the knee joint of a rabbit. In the vitreous body of a pig eye, swarms consisting of smooth spiral nanorobots have been driven to the retina. Under the guidance of X-rays, magnetic particle swarms have shown the ability to reach target areas in the liver of a rat and the kidney of a pig. However, due to factors such as the non-fluid environment of the lungs, the mucus layer, and the irregular bronchial tree structure, active microrobotic swarms face significant challenges in targeted delivery to the lungs.

[0053] In order to solve the above technical problems, the present application provides a lung deep layer targeted delivery method. The method comprises the following steps: preparing microgel particles containing magnetic microparticles, developing particles, and cargos, and combining the prepared microgel particles to obtain a microrobot swarm; controlling the motion, climbing, and reconstruction of the microrobot swarm in a non-fluid environment to realize motion in a pipe environment with holes; and controlling the motion of the microrobot swarm in a lung sample under the guidance of X-rays to deliver the microrobot swarm to a target bronchus of the lung sample; or controlling the delivery of the microrobot swarm in a target lung under the guidance of computed tomography imaging and releasing the wrapped cargos in the target bronchus.

[0054] As shown in FIG. 1, the present application provides a lung deep layer targeted delivery method, comprising the following steps:

[0055] In step S100, microgel particles containing magnetic microparticles, developing particles, and cargos are prepared, and the prepared microgel particles are combined to obtain a microrobot swarm.

[0056] In the embodiment, the deep lung targeted delivery method is realized based on a micro-robot cluster, which contains magnetic particles, developing particles and microgel particles of cargos; the micro-robot cluster is used for movement, climbing and reconstruction in a non-fluid environment, movement in a porous pipe environment, movement in a lung sample under the guidance of X-ray, delivery of cargos to a target bronchus of the lung sample, or delivery in a target lung under the guidance of computer tomography imaging and release of the encapsulated cargos in the target bronchus.

[0057] In the embodiment, the micro-robot cluster is driven or cooperated with a permanent magnet for controlling the movement direction and shape of the micro-robot cluster, an X-ray imaging device for observing bronchus distribution using X-ray imaging to determine the delivery path and the driving mode of the permanent magnet, a computer tomography scanner for scanning a target lung and reconstructing the three-dimensional structure of bronchus and planning the delivery path, and a bronchoscope for quickly deploying the micro-robot cluster from outside to the main bronchus.

[0058] In the embodiment, the core of the formation, reconstruction, movement and delivery capability of the micro-robot cluster for deep lung targeted delivery lies in the design of microgel particles, the design and on-demand switching of external driving magnetic field, and the combination with medical imaging modes.

[0059] It can be understood that in the embodiment, the micro-robot cluster can be used for movement, climbing and reconstruction in a non-fluid environment (for example, in a pipe structure) to realize movement in a porous pipe environment, movement in a lung sample under the guidance of X-ray, delivery of cargos to a target bronchus of the lung sample, or delivery in a target lung under the guidance of computer tomography imaging and release of the encapsulated cargos in the target bronchus.

[0060] In the embodiment, before controlling the micro-robot cluster to perform deep lung targeted drug delivery as described above, the micro-robot cluster needs to be prepared.

[0061] Specifically, the micro-robot cluster is composed of microgel particles, as shown in FIG. 2, which include a hydrogel network, silica-encapsulated magnetic particles, drugs and developing particles; wherein the developing particles can be equipped as needed; in the preparation process, the microgel particles in the micro-robot cluster can only contain magnetic particles, the microgel particles in the micro-robot cluster can also contain magnetic particles (i.e. developing particles), and the microgel particles in the micro-robot cluster can also contain red fluorescent dye and developing particles.

[0062] In the embodiment, the microgel particles contain magnetic particles and a large amount of water, which makes it possible for the microgel particles to form clusters in a non-fluid environment. Moreover, the use of silica-coated magnetic particles ensures the biocompatibility of the formed microgel particles. The magnetic particles contained in the microgel particles make the microgel particles responsive to an external magnetic field and subject to magnetic interaction from other particles. Meanwhile, the large amount of water contained in the microgel particles makes the particles subject to capillary forces and thus attracted to each other. Therefore, under an external rotating magnetic field, the microgel particles rotate in a non-fluid environment, contact other particles and are attracted to each other, and form a layered micro-robot cluster.

[0063] As shown in FIG. 1, the embodiment of the present application provides a method for deep lung targeted delivery, comprising the following steps:

[0064] In step S200, the motion, climbing and reconfiguration of the micro-robot cluster in a non-fluid environment are controlled to realize the motion in a perforated pipe environment.

[0065] In the embodiment, the micro-robot cluster is mainly used to realize the motion, climbing and reconfiguration in a non-fluid environment (for example, in a pipe structure), so as to realize the motion in a perforated pipe environment. Specifically, under the action of an external rotating magnetic field and an oscillating magnetic field, the motion and reversible shape reconfiguration of the micro-robot cluster in a tortuous and air-filled environment are controlled, and the micro-robot cluster climbs the wall, so as to realize targeted delivery.

[0066] Specifically, in one implementation manner of the embodiment, step S200 comprises the following steps:

[0067] In step S201, the micro-robot cluster is placed on a platform above a permanent magnet.

[0068] In step S202, the rotating and translating motion of the permanent magnet is controlled to change the magnitude and direction of the gradient force applied to the micro-robot cluster, so that the micro-robot cluster follows the permanent magnet to perform the translating motion.

[0069] In step S203, when the micro-robot cluster moves in the pipe structure, the rotating permanent magnet is slowly moved around the outer surface of the pipe, so that the micro-robot cluster climbs the wall.

[0070] In step S204, the angle of the permanent magnet is adjusted, and the oscillating motion is performed, so that the particles in the micro-robot cluster are gathered in the vertical direction, and the shape of the micro-robot cluster is converted into a columnar structure.

[0071] In one implementation manner of the embodiment, step S204 comprises the following steps:

[0072] Step S204a, adjust the angle of the permanent magnet, so that the magnetization axis of the permanent magnet is perpendicular to the plane where the micro-robot cluster is located, and perform oscillation movement, to convert the micro-robot cluster from a planar structure to a columnar structure, and reduce the coverage area of the micro-robot cluster.

[0073] Step S205, when the micro-robot cluster is in the columnar structure, control the micro-robot cluster to move in the pipe environment with holes by slowly moving the permanent magnet.

[0074] In this embodiment, an external driving magnetic field is used to realize the movement and shape reconstruction of the micro-robot cluster. As shown in FIG. 3, FIG. 3(a) is a schematic diagram of the generation of the micro-robot cluster, by rotating the external permanent magnet, the aggregation of the microgel particles containing magnetic particles can be controlled, so as to form the micro-robot cluster; FIG. 3(b) is a schematic diagram of the movement of the micro-robot cluster, by translating the external permanent magnet, the translational movement of the cluster in the tortuous and air-filled environment is realized.

[0075] As shown in FIG. 4, FIG. 4(a) is a schematic diagram of the shape reconstruction of the micro-robot cluster, by changing the angle of the permanent magnet, so that the magnetization axis is perpendicular to the plane where the cluster is located, and adjusting the permanent magnet to perform oscillation movement at a preset frequency and oscillation angle, the vertical arrangement of the microgel particles is realized, and the shape of the cluster is successfully changed from a layered structure to a columnar structure; FIG. 4(b) is a schematic diagram of the movement of the micro-robot cluster in the pipe environment with holes, by moving the external permanent magnet, the direction and size of the magnetic gradient force applied to the micro-robot cluster are changed, and the translational, climbing and lifting movement of the cluster in the tortuous and air-filled environment is realized.

[0076] As an example, in this embodiment, the specific implementation steps of the movement, climbing and reconstruction of the micro-robot cluster in the non-fluid environment are as follows:

[0077] a. Prepare microgel particles containing magnetic particles, and place the micro-robot cluster composed of the microgel particles above the platform of the permanent magnet.

[0078] b. Control the permanent magnet to perform rotation and translation movement, change the size and direction of the gradient force applied to the cluster, and make the cluster follow the permanent magnet to perform translational movement.

[0079] c. When the cluster moves in the pipe structure, slowly move the rotating permanent magnet around the outer surface of the pipe, so that the cluster climbs the wall surface.

[0080] d. Adjust the angle of the permanent magnet, so that the magnetization axis is perpendicular to the plane where the cluster is located, and perform oscillation movement, to change the magnetic interaction between the particles, make the particles aggregate in the vertical direction, thereby convert the cluster from a planar structure to a columnar structure, and reduce the coverage area of the cluster.

[0081] e.When the cluster is in a columnar structure, by slowly moving the permanent magnet, the controllable movement of the columnar cluster can be realized, so as to move in the pipe environment with holes.

[0082] In the embodiment, by applying the rotating permanent magnet, the magnetic microgel particles can form a planar micro-robot cluster in a non-fluid environment, and by moving the external permanent magnet, the cluster can be guided to move horizontally and climb as needed; and by controlling the permanent magnet to perform oscillation movement, the planar cluster can be converted into a columnar cluster to reduce the coverage area.

[0083] As shown in FIG. 1, the embodiment of the present application provides a deep lung targeted delivery method, comprising the following steps:

[0084] In step S300, the micro-robot cluster is controlled to move in the lung sample under the guidance of X-ray, and the micro-robot cluster is delivered to the target bronchus of the lung sample; or the micro-robot cluster is controlled to be delivered in the target lung under the guidance of computer tomography imaging, and the wrapped goods are released in the target bronchus.

[0085] In the embodiment, the micro-robot cluster can also be used for targeted delivery and development in an ex vivo lung sample; by setting the micro-robot cluster wrapped with development particles, the micro-robot cluster can be positioned and tracked by medical imaging. Under the guidance of X-ray, the micro-robot cluster is guided as needed in an ex vivo lung sample (for example, an ex vivo pig lung) with a mucus layer or a fluid lung model, as shown in FIG. 5, which is a schematic diagram of delivery of the micro-robot cluster in an ex vivo pig lung under the guidance of X-ray imaging.

[0086] Specifically, in an implementation manner of the embodiment, step S300 comprises the following steps:

[0087] In step S311, the lung sample is placed under an X-ray imaging device;

[0088] In step S312, the bronchus distribution of the lung sample is observed using X-ray imaging, and the delivery path and the permanent magnet driving mode are determined;

[0089] In step S313, the magnetic microgel particles of the micro-robot cluster are filled into a catheter, and the catheter is placed in the lumen of a bronchoscope, and the micro-robot cluster is deployed to the main bronchus;

[0090] In step S314, the bronchoscope is removed, a rotating permanent magnet is applied, and the permanent magnet is slowly moved along the predetermined path to guide the movement of the micro-robot cluster;

[0091] Step S315, according to the target bronchus type of the lung sample, guiding the micro-robot swarm to move from the side of the entrance of the downward bronchus, or moving the micro-robot swarm from the bottom surface to the upper surface until moving to the target bronchus.

[0092] In an implementation manner of the embodiment, step S305 comprises the following steps:

[0093] Step S315a, when encountering a downward bronchus, switching the permanent magnet driving mode to a shaking mode, changing the shape of the micro-robot swarm to reduce the swarm coverage area, and guiding the micro-robot swarm to move from the side of the entrance of the downward bronchus;

[0094] Step S315b, when an upwardly inclined bronchus is the target bronchus, placing the rotating permanent magnet above the micro-robot swarm, moving the micro-robot swarm from the bottom surface to the upper surface until moving to the target bronchus.

[0095] As an example, in the embodiment, the specific implementation steps of the delivery of the micro-robot swarm in an ex vivo pig lung are as follows:

[0096] a. Prepare magnetic microgel particles containing tiny particles (developing particles), and place an ex vivo pig lung under an X-ray imaging device.

[0097] b. Observe the bronchus distribution using X-ray imaging, and determine the delivery path and the permanent magnet driving mode.

[0098] c. Fill the magnetic microgel particles into a catheter, and place the catheter in the bronchoscope lumen, so as to quickly deploy the micro-robot swarm to the main bronchus under the assistance of the bronchoscope.

[0099] d. Remove the bronchoscope, apply the rotating permanent magnet, and slowly move the permanent magnet along the predetermined path to guide the movement of the swarm.

[0100] e. When encountering a downward bronchus, switch the permanent magnet driving mode to a shaking mode, change the shape of the swarm to reduce the swarm coverage area, and guide the swarm to move from the side of the entrance of the downward bronchus, so as to avoid the particles falling into the downward bronchus.

[0101] f. When an upwardly inclined bronchus is the target bronchus, place the rotating permanent magnet above the swarm, move the swarm from the bottom surface to the upper surface, and further move the permanent magnet towards the inclined bronchus, so as to move the swarm on the upper surface to the target bronchus.

[0102] In the embodiment, the micro-robot cluster can be filled into a catheter, so that the micro-robot cluster can be quickly deployed from the outside to the main bronchus of the lung using a bronchoscope, and the micro-robot cluster can wrap a developing particle, so that the real-time tracking of the cluster can be performed using an X-ray imaging technology in the presence of mucus in an ex vivo pig lung, and the targeted delivery can be achieved using an external magnetic field guide.

[0103] In the embodiment, the micro-robot cluster is used for deep targeted delivery in a target lung model or sample, and develops according to a delivery position. By arranging a micro-robot cluster containing a red fluorescent dye and a developing particle, the micro-robot cluster can be successfully delivered to a deep target bronchus of the lung under computer tomography imaging, and the ability of the micro-robot cluster to reconstruct on demand to avoid microgel particles from entering a non-target bronchus and accurately enter an inclined bronchus through a climbing motion is verified, as shown in FIG. 6, which is a schematic diagram of delivery of a micro-robot cluster in a target pig lung sample under computer tomography imaging guidance. In addition, the fluorescent dye wrapped by the micro-robot cluster is also successfully delivered and released to the target bronchus.

[0104] Specifically, in an implementation form of the embodiment, the step S300 includes the following steps:

[0105] The step S321 includes the following steps:

[0106] The step S322 includes the following steps:

[0107] The step S323 includes the following steps:

[0108] The step S324 includes the following steps:

[0109] The step S325 includes the following steps:

[0110] In an implementation form of the embodiment, the step S325 includes the following steps:

[0111] Step S325a, when encountering a downward bronchus, the permanent magnet is made to perform an oscillating motion to change the shape of the micro-robot cluster and reduce the coverage area, guiding the micro-robot cluster to pass through the downward bronchus;

[0112] Step S325b, when the micro-robot cluster reaches the deep target bronchus, the micro-robot cluster is fixed in the target bronchus using the permanent magnet, and the wrapped cargo is released.

[0113] In the embodiment, the fluid lung environment can be simulated by setting a target lung model or sample (for example, an ex vivo pig lung sample), and simulating continuous mucus secretion and periodic expansion and contraction motion therein, thereby simulating the continuous secretion of mucus and periodic expansion and contraction motion of the pig lung in the pig body.

[0114] As an example, in the embodiment, the specific implementation steps of the delivery of the micro-robot cluster in the target lung model or sample are as follows:

[0115] a. Prepare microgel particles containing red fluorescent dye and developing particles.

[0116] b. Place the target lung model or sample on the platform.

[0117] c. Scan the target lung using a computer tomograph, and reconstruct the three-dimensional structure of the bronchus and plan the delivery path.

[0118] d. Place the tracheal tube into the trachea orally, and insert the bronchoscope into the main bronchus through the tracheal tube.

[0119] e. Fill the cluster particles into the catheter, and insert the catheter into the bronchoscope lumen, thereby delivering the cluster to the main bronchus.

[0120] f. Apply and move the permanent magnet to guide the cluster motion, and use the computer tomograph to determine the cluster position during the movement, thereby adjusting the position and angle of the permanent magnet.

[0121] g. When encountering a downward bronchus, the permanent magnet is made to perform an oscillating motion to change the shape of the cluster and reduce the coverage area of the cluster, further guiding the cluster to pass through the downward bronchus, and ensuring the integrity of the cluster.

[0122] h. After the cluster reaches the deep target bronchus, the cluster is fixed at the target position using the permanent magnet to release the wrapped fluorescent dye.

[0123] The micro-robot cluster is delivered to a target bronchus in a deep lung and releases the wrapped goods, thereby verifying the ability of the micro-robot cluster to reconstruct on demand to avoid microgel particles from entering non-target bronchus and to accurately enter an inclined bronchus through climbing movement.

[0124] The technical scheme in the embodiment has the following effects:

[0125] The micro-robot cluster is delivered to a target bronchus in a deep lung and releases the wrapped goods, thereby verifying the ability of the micro-robot cluster to reconstruct on demand to avoid microgel particles from entering non-target bronchus and to accurately enter an inclined bronchus through climbing movement.

[0126] Exemplary apparatus

[0127] As shown in FIGS. 2-6, the micro-robot cluster for implementing the lung deep targeted delivery method in the above embodiment includes:

[0128] The micro-robot cluster includes microgel particles containing magnetic particles, developing particles and goods; the micro-robot cluster is used for movement, climbing and reconstruction in a non-fluid environment, to move in a porous pipeline environment; is used for movement in a lung sample under the guidance of X-ray, to deliver goods to a target bronchus in the lung sample; or is used for delivery in a target lung under the guidance of computer tomography imaging, and releases the wrapped goods in the target bronchus.

[0129] In the embodiment, the micro-robot cluster is driven or cooperated with a permanent magnet for controlling the moving direction and shape of the micro-robot cluster, an X-ray imaging device for observing the bronchial distribution using X-ray imaging to determine the delivery path and the driving mode of the permanent magnet, a computer tomography scanner for scanning the target lung and reconstructing the three-dimensional structure of the bronchus and planning the delivery path, and a bronchoscope for quickly deploying the micro-robot cluster from the outside to the main bronchus.

[0130] In the embodiment, the core of the formation, reconstruction, motion and delivery capability of the micro-robot cluster for deep lung targeted delivery lies in the design of the microgel particles, the design and on-demand switching of the external driving magnetic field, and the combination with medical imaging modes.

[0131] It can be understood that, in the embodiment, the micro-robot cluster can be used for motion, climbing and reconstruction in a non-fluid environment (for example, in a pipe structure), so as to realize motion in a pipe environment with holes; can also be used for motion in a lung sample under the guidance of X-ray, delivery of goods to a target bronchus of the lung sample; or can be used for delivery in a target lung under the guidance of computer tomography imaging, and release of the wrapped goods in a target bronchus.

[0132] In the embodiment, before the micro-robot cluster is controlled to perform deep lung targeted drug delivery as described above, the micro-robot cluster also needs to be prepared.

[0133] Specifically, the micro-robot cluster is composed of microgel particles, as shown in FIG. 2, which include a hydrogel network, silica-coated magnetic micro-particles, drugs and developing particles; wherein the developing particles can be equipped as needed; in the preparation process, the microgel particles in the micro-robot cluster can only contain magnetic particles, the microgel particles in the micro-robot cluster can also contain magnetic particles (i.e. developing particles), and the microgel particles in the micro-robot cluster can also contain red fluorescent dye and developing particles.

[0134] In the embodiment, the microgel particles contain magnetic particles and a large amount of water, which makes the formation of the cluster in a non-fluid environment possible. Moreover, by using silica-coated magnetic particles, the biocompatibility of the formed microgel particles is ensured. The inclusion of magnetic particles makes the microgel particles responsive to the external magnetic field and the particles subject to magnetic interaction from other particles. At the same time, due to the large amount of water contained in the microgel particles, there is a liquid bridge between adjacent particles, so that the particles are subject to capillary forces and attract each other. Therefore, under the external rotating magnetic field, the microgel particles rotate in the non-fluid environment, contact with other particles and attract each other, forming a layered micro-robot cluster.

[0135] The external driving magnetic field is used to realize the motion and shape reconstruction of the micro-robot cluster. By moving the external permanent magnet, the direction and size of the magnetic gradient force applied to the micro-robot cluster are changed, realizing the translational, climbing and lifting motion of the cluster in the tortuous and air-filled environment. By changing the angle of the permanent magnet, making its magnetization axis perpendicular to the plane where the cluster is located, and adjusting the permanent magnet to perform oscillation motion at a preset frequency and oscillation angle, the vertical arrangement of the microgel particles is realized, and the shape of the cluster is successfully changed from a layered structure to a columnar structure.

[0136] The medical imaging mode includes X-ray imaging and computer tomography imaging, which provides the possibility for the targeted delivery of the micro-robot cluster in the ex vivo and in vivo pig lung. Considering the air-filled environment in the ex vivo and in vivo pig lung, X-ray imaging and computer tomography imaging are used for cluster guidance. By wrapping the developing particles into the microgel particles, the cluster can be developed in the medical imaging mode to detect the position of the cluster in the pig lung, and then the external magnetic field mode can be adjusted according to the local environment around the cluster, realizing the motion, deformation and targeted delivery of the cluster in the ex vivo pig lung with mucus layer and the pig lung with continuously secreting mucus and lung contraction and expansion characteristics.

[0137] The embodiment adopts the above technical solutions and has the following effects:

[0138] The embodiment proposes a micro-robot cluster for deep lung targeted delivery, which can control the cluster to perform controllable motion and reversible shape reconstruction in a tortuous and air-filled environment under the action of an external rotating magnetic field and an oscillating magnetic field, and climb the wall. By wrapping the developing particles, the micro-robot cluster can be positioned and tracked by medical imaging. Under the guidance of X-ray, the micro-robot cluster is realized in the ex vivo pig lung with mucus layer. Under the computer tomography imaging, the micro-robot cluster is successfully delivered to the deep target bronchus in the pig lung, verifying the ability of the cluster to reconstruct on demand to avoid microgel particles entering non-target bronchus, and accurately entering the inclined bronchus through climbing motion. In addition, the fluorescent dye wrapped by the micro-robot cluster is also successfully delivered and released to the target bronchus.

[0139] A person of ordinary skill in the art can understand that all or part of the processes in the above-mentioned embodiment methods can be completed by a computer program instructing related hardware. The computer program can be stored in a non-volatile storage medium, and when executed, can include the processes of the above-mentioned embodiments. Any reference to memory, storage, database or other medium used in the embodiments provided by the present application can include non-volatile and volatile memory.

[0140] In summary, the application provides a lung deep layer targeted delivery method and micro robot cluster, the method comprising: preparing microgel particles containing magnetic microparticles, developing particles and cargos, and combining the prepared microgel particles to obtain a micro robot cluster; controlling the motion, climbing and reconstruction of the micro robot cluster in a non-fluid environment to realize motion in a pipe environment with holes; controlling the motion of the micro robot cluster in a lung sample under the guidance of X-ray to deliver the micro robot cluster to a target bronchus of the lung sample; or controlling the delivery of the micro robot cluster in the target lung under the guidance of computer tomography imaging, and releasing the wrapped cargos in the target bronchus; the micro robot cluster provided by the application can realize targeted delivery in the lung environment full of air, the lung environment with a mucus layer and the target bronchus in the lung deep layer.

[0141] It should be understood that the application is not limited to the above examples, and can be improved or changed by those of ordinary skill in the art according to the above description, and all these improvements and changes shall belong to the protection scope of the appended claims of the application.

Claims

1. A method of deep lung targeted delivery, comprising, The deep lung targeted delivery method comprises: Preparation of microgel particles containing magnetic microparticles, developing particles and cargos, and combination of the prepared microgel particles to obtain a micro-robot cluster; Controlling the motion, climbing and reconfiguration of the micro-robot cluster in a non-fluid environment to realize the motion in a porous pipe environment; Controlling the motion of the micro-robot cluster in the lung sample under the guidance of X-ray, delivering the micro-robot cluster to the target bronchus of the lung sample; or controlling the delivery of the micro-robot cluster in the target lung under the guidance of computer tomography imaging, and releasing the wrapped cargos in the target bronchus.

2. The deep lung targeted delivery method according to claim 1, wherein, The control of the motion, climbing and reconfiguration of the micro-robot cluster in a non-fluid environment to realize the motion in a porous pipe environment comprises: Placing the micro-robot cluster on a platform above a permanent magnet; Controlling the rotating and translating motion of the permanent magnet to change the gradient force size and direction applied to the micro-robot cluster, and making the micro-robot cluster follow the translating motion of the permanent magnet; When the micro-robot cluster moves in the pipe structure, slowly moving the rotating permanent magnet around the outer surface of the pipe to make the micro-robot cluster climb the wall surface; Adjusting the angle of the permanent magnet and performing oscillation motion to make the particles in the micro-robot cluster gather in the vertical direction, and converting the shape of the micro-robot cluster into a columnar structure; When the micro-robot cluster is in the columnar structure, controlling the motion of the micro-robot cluster in the porous pipe environment by slowly moving the permanent magnet.

3. The deep lung targeted delivery method according to claim 2, wherein, The adjustment of the angle of the permanent magnet and the oscillation motion to make the particles in the micro-robot cluster gather in the vertical direction, and the conversion of the shape of the micro-robot cluster into a columnar structure comprises: Adjusting the angle of the permanent magnet to make the magnetization axis of the permanent magnet perpendicular to the plane where the micro-robot cluster is located, and performing oscillation motion to convert the micro-robot cluster from a planar structure to a columnar structure, and reduce the coverage area of the micro-robot cluster.

4. The deep lung targeted delivery method according to claim 2, wherein, The control of the motion of the micro-robot cluster in the lung sample under the guidance of X-ray to deliver the micro-robot cluster to the target bronchus of the lung sample comprises: Placing the lung sample under an X-ray imaging device; Observing the bronchus distribution of the lung sample using X-ray imaging to determine the delivery path and permanent magnet driving mode; Filling the micro-robot cluster into a catheter, and placing the catheter in the bronchoscope lumen to deploy the micro-robot cluster to the main bronchus; Removing the bronchoscope, applying a rotating permanent magnet, and slowly moving the permanent magnet along the predetermined path to guide the motion of the micro-robot cluster; According to the type of target bronchus of the lung sample, guiding the micro-robot cluster to move beside the entrance of the downward bronchus, or making the micro-robot cluster move from the bottom surface to the upper surface until moving to the target bronchus.

5. The deep lung targeted delivery method according to claim 4, wherein, The guiding of the micro-robot cluster to move beside the entrance of the downward bronchus according to the type of target bronchus of the lung sample comprises: When encountering a downward bronchus, switch the permanent magnet driving mode to a shaking mode, change the shape of the micro-robot cluster to reduce the cluster coverage area, and guide the micro-robot cluster to move from the entrance of the downward bronchus.

6. The deep lung targeted delivery method according to claim 4, wherein, The moving of the micro-robot cluster from the bottom surface to the upper surface until moving to the target bronchus comprises: When the upward inclined bronchus is the target bronchus, place the rotating permanent magnet above the micro-robot cluster, and move the micro-robot cluster from the bottom surface to the upper surface until moving to the target bronchus.

7. The deep lung targeted delivery method according to claim 2, wherein, The controlling of the micro-robot cluster to deliver in the target lung under the guidance of computed tomography imaging and release the wrapped cargo in the target bronchus comprises: Scan the target lung using a computed tomography scanner, and perform bronchial three-dimensional structure reconstruction and delivery path planning; Place a tracheal tube into the lung bronchus through the mouth, and insert a bronchoscope into the main bronchus through the tracheal tube; Fill the micro-robot cluster into a catheter, and insert the catheter into the bronchoscope lumen to deliver the micro-robot cluster to the main bronchus of the target lung; Apply and move the permanent magnet to guide the movement of the micro-robot cluster, and use the computed tomography to determine the position of the micro-robot cluster in the moving gap, adjust the position and angle of the permanent magnet; According to the position of the micro-robot cluster, adjust the driving mode of the permanent magnet to control the micro-robot cluster to release the wrapped cargo in the target bronchus.

8. The deep lung targeted delivery method according to claim 7, wherein, The controlling of the micro-robot cluster to deliver in the target lung under the guidance of computed tomography imaging and release the wrapped cargo in the target bronchus comprises: When encountering a downward bronchus, make the permanent magnet perform a shaking movement to change the shape of the micro-robot cluster and reduce the coverage area, and guide the micro-robot cluster to pass through the downward bronchus; When the micro-robot cluster reaches the deep target bronchus, use the permanent magnet to fix the micro-robot cluster in the target bronchus and release the wrapped cargo.

9. A micro-robotic swarm for use in the method of deep lung targeted delivery according to any one of claims 1 to 8, characterized in that, The micro-robot cluster comprises: The micro-robot cluster comprises magnetic particles, developing particles, and microgel particles of cargo; the micro-robot cluster is used for movement, climbing, and reconstruction in a non-fluid environment, realizes movement in a pipe environment with holes, is used for movement in a lung sample under the guidance of X-rays, delivers cargo to a target bronchus of the lung sample, or is used for delivery in a target lung under the guidance of computed tomography imaging and release of the wrapped cargo in the target bronchus.

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