Lung deep targeted delivery method and micro-robot cluster

Abstract

The invention discloses a lung deep targeted delivery method and a micro-robot cluster, and the method comprises the following steps: preparing microgel particles containing magnetic particles, developing particles and cargos, and combining the prepared microgel particles to obtain the micro-robot cluster; the micro-robot cluster is controlled to move, climb and reconstruct in a non-fluid environment, so that the micro-robot cluster moves in a pipeline environment with holes; controlling the micro-robot cluster to move in the lung sample under the guidance of X-rays, and delivering the micro-robot cluster to a target bronchus of the lung sample; or the micro-robot cluster is controlled to be delivered in the target lung under the guidance of computed tomography imaging, and the wrapped goods are released in the target bronchus; the micro robot cluster provided by the invention can realize targeted delivery in a lung environment full of air, a lung environment with a mucus layer and a lung deep target bronchus.

Description

Technical Field

[0001] The present invention relates to the field of micro-nano robot technology, and in particular to a deep lung targeted delivery method and a micro-robot cluster. Background Art

[0002] Pulmonary delivery of therapeutic drugs has become a focus of treatment for various lung diseases, such as lung cancer, cystic fibrosis, and pneumonia. Although systemic routes of administration such as oral and intravenous injection can effectively deliver drugs to the lungs through the blood circulation, they often lead to drug accumulation and toxicity in non-target sites. The inhalation route allows drugs to bypass first-pass metabolism in the liver, which helps drugs to act in the lungs, but faces the problem of non-selective distribution of inhaled drugs in the lungs, which has adverse effects on healthy tissues. To achieve precise local drug delivery in the lungs, bronchoscopes have been used for drug instillation or direct injection to deliver drugs close to the target lesion. However, the movement flexibility of traditional bronchoscopes is limited and it is difficult to adapt to the tortuous and narrow bronchial tree in the lungs. Therefore, new technologies need to be developed to accurately deliver drugs locally to target lesions in the lungs.

[0003] Active microrobot swarms offer a promising solution for delivering therapeutic drugs to hard-to-reach lesions in the human body. Microrobot swarms have demonstrated their ability to deliver therapeutic drugs by providing remote controllability, motion flexibility, and the ability to enhance contrast in medical imaging. Magnetic microrobot swarms have achieved targeted delivery in different physiological environments such as the knee, eye, and blood vessels. Driven by gradient magnetic fields, magnetic microscaffold swarms have successfully delivered stem cells to cartilage defects in rabbit knees. In the vitreous of pig eyes, swarms of smooth helical nanorobots have been driven to the retina. Under the guidance of X-rays, magnetic particle swarms have demonstrated the ability to reach target areas in rat liver and pig kidney. However, due to the non-fluid environment, mucus layer, and irregular bronchial tree structure of the lungs, the targeted delivery of active microrobot swarms in the lungs faces significant challenges.

[0004] Therefore, the prior art needs to be improved. Summary of the invention

[0005] The technical problem to be solved by the present invention is that, in view of the defects of the prior art, the present invention provides a deep lung targeted delivery method and a micro-robot cluster to solve the problem that the existing micro-robot clusters are unable to perform precise targeted drug delivery in the lung gas environment.

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

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

[0008] preparing microgel particles comprising magnetic particles, developing particles and cargo, and combining the prepared microgel particles to obtain a microrobot cluster;

[0009] Controlling the movement, climbing and reconstruction of the micro-robot cluster in a non-fluid environment to achieve movement in a perforated pipe environment;

[0010] Control the microrobot cluster to move in the lung sample under the guidance of X-rays, and deliver the microrobot cluster to the target bronchus of the lung sample; or control the microrobot cluster to deliver in the target lung under the guidance of computed tomography imaging, and release the encapsulated cargo in the target bronchus.

[0011] In one implementation, controlling the movement, climbing, and reconstruction of the micro-robot cluster in a non-fluid environment to achieve movement in a perforated pipe environment includes:

[0012] placing the microrobot cluster on a platform above a permanent magnet;

[0013] Controlling the permanent magnet to perform rotation and translation motion, changing 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 translation motion;

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

[0015] Adjusting the angle of the permanent magnet and performing an oscillating motion to cause particles in the microrobot cluster to gather in a vertical direction, thereby transforming the shape of the microrobot cluster into a columnar structure;

[0016] When the micro-robot cluster is in the columnar structure, the micro-robot cluster is controlled to move in a pipe environment with holes by slowly moving the permanent magnet.

[0017] In one implementation, adjusting the angle of the permanent magnet and performing an oscillating motion to aggregate particles in the microrobot cluster in a vertical direction and transforming the shape of the microrobot cluster into a columnar structure includes:

[0018] The angle of the permanent magnet is adjusted so that the magnetization axis of the permanent magnet is perpendicular to the plane where the micro-robot cluster is located, and an oscillating motion is performed to transform the micro-robot cluster from a planar structure to a columnar structure and reduce the coverage area of ​​the micro-robot cluster.

[0019] In one implementation, controlling the microrobot cluster to move in the lung sample under the guidance of X-rays and delivering the microrobot cluster to the target bronchus of the lung sample includes:

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

[0021] Using X-ray imaging to observe the bronchial distribution of the lung sample, determine the delivery path and permanent magnet driving mode;

[0022] Filling the microrobot cluster into a catheter, placing the catheter in the lumen of a bronchoscope, and deploying the microrobot cluster to the main bronchus;

[0023] The bronchoscope is removed, a rotating permanent magnet is applied, and the permanent magnet is slowly moved along a predetermined path to guide the movement of the micro-robot cluster;

[0024] According to the target bronchus type of the lung sample, the micro-robot cluster is guided to move from the entrance of the descending bronchus, or the micro-robot cluster is moved from the bottom surface to the upper surface until it moves to the target bronchus.

[0025] In one implementation, guiding the microrobot cluster to move from the entrance of the descending bronchus according to the target bronchus type of the lung sample includes:

[0026] When encountering a downward bronchus, the permanent magnet driving mode is switched to an oscillation mode, the shape of the micro-robot cluster is changed to reduce the cluster coverage area, and the micro-robot cluster is guided to move beside the entrance of the downward bronchus.

[0027] In one implementation, the step of moving the micro-robot cluster from the bottom surface to the upper surface until it reaches the target bronchus comprises:

[0028] When the upwardly tilted bronchus is the target bronchus, a rotating permanent magnet is placed above the micro-robot cluster to move the micro-robot cluster from the bottom surface to the upper surface until it moves to the target bronchus.

[0029] In one implementation, controlling the microrobot cluster to deliver in a target lung under the guidance of computed tomography imaging and releasing the encapsulated cargo in a target bronchus comprises:

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

[0031] An endotracheal tube is placed through the mouth into the trachea of ​​the lung, and a bronchoscope is inserted through the endotracheal tube into the mainstem bronchus;

[0032] Filling the microrobot cluster into a catheter, inserting the catheter into the lumen of a bronchoscope, and delivering the microrobot cluster to the main bronchus of the target lung;

[0033] Applying and moving the permanent magnet to guide the movement of the micro-robot cluster, and using the computed tomography to determine the position of the micro-robot cluster during the movement interval, and adjusting the position and angle of the permanent magnet;

[0034] According to the position of the micro-robot cluster, the driving mode of the permanent magnet is adjusted to control the micro-robot cluster to release the wrapped cargo in the target bronchus.

[0035] In one implementation, adjusting the driving mode of the permanent magnet according to the position of the micro-robot cluster to control the micro-robot cluster to release the wrapped cargo in the target bronchus includes:

[0036] When encountering the downward bronchus, the permanent magnet is made to oscillate to change the shape of the micro-robot cluster and reduce the coverage area, so as to guide the micro-robot cluster to cross the downward bronchus;

[0037] When the microrobot cluster reaches the deep target bronchus, the microrobot cluster is fixed to the target bronchus using the permanent magnet and the encapsulated cargo is released.

[0038] In a second aspect, the present invention provides a micro-robot cluster for implementing the deep lung targeted delivery method described in the first aspect, wherein the micro-robot cluster comprises:

[0039] A microrobot cluster, wherein the microrobot cluster contains magnetic particles, imaging particles and microgel particles of cargo; the microrobot cluster is used for movement, climbing and reconstructing in a non-fluid environment to achieve movement in a perforated pipe environment; is used for moving in a lung sample under the guidance of X-rays and delivering 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 releasing the encapsulated cargo in the target bronchus.

[0040] The present invention adopts the above technical solution to achieve the following effects:

[0041] The present invention prepares microgel particles containing magnetic particles, developing particles and cargo, and combines the prepared microgel particles to obtain a microrobot cluster; and by controlling the movement, climbing and reconstruction of the microrobot cluster in a non-fluid environment, the microrobot cluster can be moved in a perforated pipe environment; and by controlling the microrobot cluster to move in a lung sample under the guidance of X-rays, the microrobot cluster can be delivered to the target bronchus of the lung sample; or the microrobot cluster is controlled to be delivered in the target lung under the guidance of computed tomography imaging, and the encapsulated cargo is released in the target bronchus; the microrobot cluster provided by the present invention can achieve targeted delivery in a lung environment filled with air, a lung environment with a mucus layer, and a target bronchus deep in the lung. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.

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

[0044] Figure 2 It is a schematic diagram of the composition of magnetic microgel particles in a preferred embodiment of the present invention.

[0045] Figure 3 (a) is a schematic diagram of microrobot cluster generation in a preferred embodiment of the present invention; Figure 3 (b) is a schematic diagram of the movement of a microrobot cluster in a preferred embodiment of the present invention.

[0046] Figure 4 (a) is a schematic diagram of shape reconstruction of a micro-robot cluster in a preferred embodiment of the present invention; Figure 4 (b) is a schematic diagram of the movement of a microrobot cluster in a perforated pipe environment in a preferred embodiment of the present invention.

[0047] Figure 5 It is a schematic diagram of the delivery of a microrobot cluster in an ex vivo pig lung under the guidance of X-ray imaging in a preferred embodiment of the present invention.

[0048] Figure 6 It is a schematic diagram of the delivery of a microrobot cluster in a target pig lung under the guidance of computed tomography imaging in a preferred embodiment of the present invention.

[0049] The purpose, features and advantages of the present invention will be further described with reference to the accompanying drawings in conjunction with the embodiments. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the present invention clearer and more specific, the present invention is further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0051] Exemplary Methods

[0052] Active microrobot swarms offer a promising solution for delivering therapeutic drugs to hard-to-reach lesions in the human body. Microrobot swarms have demonstrated their ability to deliver therapeutic drugs by providing remote controllability, motion flexibility, and the ability to enhance contrast in medical imaging. Magnetic microrobot swarms have achieved targeted delivery in different physiological environments such as the knee, eye, and blood vessels. Driven by gradient magnetic fields, magnetic microscaffold swarms have successfully delivered stem cells to cartilage defects in rabbit knees. In the vitreous of pig eyes, swarms of smooth helical nanorobots have been driven to the retina. Under the guidance of X-rays, magnetic particle swarms have demonstrated the ability to reach target areas in rat liver and pig kidney. However, due to the non-fluid environment, mucus layer, and irregular bronchial tree structure of the lungs, the targeted delivery of active microrobot swarms in the lungs faces significant challenges.

[0053] In response to the above technical problems, an embodiment of the present invention provides a method for deep lung targeted delivery, which can obtain a microrobot cluster by preparing microgel particles containing magnetic particles, developing particles and cargo, and combining the prepared microgel particles; and by controlling the movement, climbing and reconstruction of the microrobot cluster in a non-fluid environment, it can achieve movement in a perforated pipe environment; and by controlling the microrobot cluster to move in a lung sample under the guidance of X-rays, the microrobot cluster can be delivered to the target bronchus of the lung sample; or the microrobot cluster can be controlled to deliver in the target lung under the guidance of computed tomography imaging, and release the encapsulated cargo in the target bronchus.

[0054] like Figure 1 As shown, an embodiment of the present invention provides a method for deep lung targeted delivery, comprising the following steps:

[0055] Step S100, preparing microgel particles containing magnetic particles, developer particles and cargo, and combining the prepared microgel particles to obtain a microrobot cluster.

[0056] In this embodiment, the deep lung targeted delivery method is implemented based on a microrobot cluster, which contains magnetic particles, imaging particles and microgel particles of cargo; the microrobot cluster is used to move, climb and reconstruct in a non-fluid environment to achieve movement in a perforated pipe environment; it is used to move in a lung sample under the guidance of X-rays to deliver cargo to the target bronchus of the lung sample; or it is used to deliver in the target lung under the guidance of computed tomography imaging and release the encapsulated cargo in the target bronchus.

[0057] In this embodiment, the micro-robot cluster is driven or used in conjunction with the following devices: a permanent magnet, used to control the movement direction and shape of the micro-robot cluster; an X-ray imaging device, used to use X-ray imaging to observe the bronchial distribution to determine the delivery path and permanent magnet driving mode; a computer tomography scanner, used to scan the target lungs, and perform bronchial three-dimensional structure reconstruction and delivery path planning; a bronchoscope, used to quickly deploy an external micro-robot cluster to the main bronchus.

[0058] In this embodiment, the formation, reconstruction, movement and delivery capabilities of the provided microrobot cluster that can be used for deep lung targeted delivery are centered on the design of microgel particles, the design and on-demand switching of the external driving magnetic field, and the combination with medical imaging modalities.

[0059] It can be understood that in this embodiment, the microrobot cluster can be used for movement, climbing and reconstructing in a non-fluid environment (for example, within a pipeline structure), thereby achieving movement in a perforated pipeline environment; it is also used to move in a lung sample under the guidance of X-rays and deliver cargo to the target bronchus of the lung sample; or to deliver in a target lung under the guidance of computed tomography imaging and release the encapsulated cargo in the target bronchus.

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

[0061] Specifically, the microrobot cluster is composed of microgel particles, such as Figure 2 As shown, the microgel particles include: a hydrogel network, silica-wrapped magnetic microparticles, drugs and developer particles; wherein the developer particles can be prepared as needed; during the preparation process, the microgel particles in the microrobot cluster may only contain magnetic particles, the microgel particles in the microrobot cluster may also contain magnetic particles (i.e. developer particles), and the microgel particles in the microrobot cluster may also contain red fluorescent dyes and developer particles.

[0062] In this embodiment, the microgel particles contain magnetic particles and a large amount of water, which makes it possible to form clusters in a non-fluid environment. In addition, by using silica to wrap the magnetic particles, the biocompatibility of the formed microgel particles is ensured. The inclusion of magnetic particles allows the microgel particles to respond to the external magnetic field and causes the particles to be subjected to magnetic interactions from other particles. At the same time, since the microgel particles contain a large amount of water, liquid bridges exist between adjacent particles, causing the particles to be subjected to capillary forces and thus attract each other. Therefore, under an external rotating magnetic field, the microgel particles rotate in a non-fluid environment, contact with other particles and attract each other, forming a layered microrobot cluster.

[0063] like Figure 1 As shown, an embodiment of the present invention provides a method for deep lung targeted delivery, comprising the following steps:

[0064] Step S200, controlling the movement, climbing and reconstruction of the micro-robot cluster in a non-fluid environment to achieve movement in a perforated pipe environment.

[0065] In this embodiment, the microrobot cluster is mainly used to achieve movement, climbing and reconstruction in a non-fluid environment (for example, within a pipeline structure), thereby achieving movement in a porous pipeline environment; specifically, under the action of an external rotating magnetic field and an oscillating magnetic field, the microrobot cluster is controlled to perform controllable movement and reversible shape reconstruction in a tortuous and air-filled environment, and climb the wall, thereby achieving targeted delivery.

[0066] Specifically, in an implementation of this embodiment, step S200 includes the following steps:

[0067] Step S201, placing the micro-robot cluster on a platform above a permanent magnet;

[0068] Step S202, controlling the permanent magnet to perform rotation and translation motion, changing 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 translation motion;

[0069] Step S203, when the micro-robot cluster moves in the pipeline structure, the rotating permanent magnet is slowly moved around the outer surface of the pipeline to enable the micro-robot cluster to climb the wall;

[0070] Step S204, adjusting the angle of the permanent magnet and performing an oscillating motion to make the particles in the micro-robot cluster gather in a vertical direction and transform the shape of the micro-robot cluster into a columnar structure;

[0071] In one implementation of this embodiment, step S204 includes the following steps:

[0072] Step S204a, adjusting 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 performing an oscillating motion to transform 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, the micro-robot cluster is controlled to move in a pipe environment with holes by slowly moving the permanent magnet.

[0074] In this embodiment, an external driving magnetic field is used to achieve the movement and shape reconstruction of the micro-robot cluster. Figure 3 As shown, Figure 3 (a) is a schematic diagram of the generation of a microrobot cluster. By rotating an external permanent magnet, the microgel particles containing magnetic microparticles can be controlled to aggregate, thereby forming the microrobot cluster; Figure 3 (b) is a schematic diagram of the motion of a microrobot cluster. By translating an external permanent magnet, the cluster can achieve translational motion in a tortuous and air-filled environment.

[0075] like Figure 4 As shown, Figure 4 (a) is a schematic diagram of the shape reconstruction of the microrobot cluster. By changing the angle of the permanent magnet so that its magnetization axis is perpendicular to the plane where the cluster is located, and adjusting the permanent magnet to oscillate at a preset frequency and oscillation angle, the vertical arrangement of the microgel particles is achieved, successfully transforming the cluster shape from a layered structure to a columnar structure. Figure 4 (b) is a schematic diagram of the movement of a microrobot cluster in a porous pipe environment. By moving the external permanent magnet, the direction and magnitude of the magnetic gradient force applied to the microrobot cluster are changed, thereby achieving translational, climbing and lifting movements of the cluster in a tortuous and air-filled environment.

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

[0077] a. Prepare microgel particles containing magnetic particles and place the microrobot cluster composed of them on a platform above a permanent magnet.

[0078] b. Control the permanent magnet to rotate and translate, change the magnitude and direction of the gradient force applied to the cluster, and make the cluster follow the permanent magnet to translate.

[0079] c. When the cluster moves in the pipe structure, the rotating permanent magnet is slowly moved around the outer surface of the pipe, allowing the cluster to climb the wall.

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

[0081] e. When the cluster is in a columnar structure, the controllable movement of the columnar cluster can be achieved by slowly moving the permanent magnet, so that it can move in a perforated pipe environment.

[0082] In this embodiment, by applying a rotating permanent magnet, the magnetic microgel particles can form a planar microrobot cluster in a non-fluid environment, and the cluster can be guided to perform translational and climbing movements as needed by moving the external permanent magnet; and by controlling the permanent magnet to perform oscillating motion, the planar cluster can be converted into a columnar cluster to reduce the coverage area.

[0083] like Figure 1 As shown, an embodiment of the present invention provides a method for deep lung targeted delivery, comprising the following steps:

[0084] Step S300, controlling the microrobot cluster to move in the lung sample under the guidance of X-rays, and delivering the microrobot cluster to the target bronchus of the lung sample; or controlling the microrobot cluster to deliver in the target lung under the guidance of computed tomography imaging, and releasing the encapsulated cargo in the target bronchus.

[0085] In this embodiment, the microrobot cluster can also be used for targeted delivery and imaging in ex vivo lung samples; by setting up a microrobot cluster wrapped with imaging particles, the microrobot cluster can be positioned and tracked by medical imaging. Under X-ray guidance, the microrobot cluster is guided on demand in an ex vivo lung sample with a mucus layer (e.g., an ex vivo pig lung) or a fluid lung model, such as Figure 5 As shown, Figure 5 Schematic diagram of X-ray imaging-guided delivery of microrobot clusters in ex vivo pig lungs.

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

[0087] Step S311, placing the lung sample under an X-ray imaging device;

[0088] Step S312, using X-ray imaging to observe the bronchial distribution of the lung sample, and determining the delivery path and permanent magnet driving mode;

[0089] Step S313, filling the magnetic microgel particles of the microrobot cluster into a catheter, placing the catheter in the lumen of a bronchoscope, and deploying the microrobot cluster to the main bronchus;

[0090] Step S314, removing the bronchoscope, applying a rotating permanent magnet, and slowly moving the permanent magnet along a predetermined path to guide the movement of the micro-robot cluster;

[0091] Step S315, according to the target bronchus type of the lung sample, guide the micro-robot cluster to move from the entrance of the lower bronchus, or make the micro-robot cluster move from the bottom surface to the upper surface until it moves to the target bronchus.

[0092] In one implementation of this embodiment, step S305 includes the following steps:

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

[0094] Step S315b, when the upwardly tilted bronchus is the target bronchus, a rotating permanent magnet is placed above the micro-robot cluster to move the micro-robot cluster from the bottom surface to the upper surface until it moves to the target bronchus.

[0095] As an example, in this embodiment, the specific implementation steps of the microrobot cluster delivery in the ex vivo pig lung are as follows:

[0096] a. Prepare magnetic microgel particles containing tantalum particles (imaging particles) and place isolated pig lungs under an X-ray imaging device.

[0097] b. Use X-ray imaging to observe the bronchial distribution and determine the delivery path and permanent magnet driving mode.

[0098] c. Fill the catheter with magnetic microgel particles and place the catheter in the lumen of the bronchoscope, so that the microrobot cluster can be quickly deployed to the main bronchus with 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 cluster movement.

[0100] e. When encountering the downward bronchus, switch the permanent magnet drive mode to the oscillation mode, change the cluster shape to reduce the cluster coverage area, and guide the cluster to move beside the entrance of the downward bronchus, thereby preventing particles from falling into the downward bronchus.

[0101] f. When the upward tilted bronchus is the target bronchus, a rotating permanent magnet is placed above the cluster to move the cluster from the bottom surface to the upper surface. The permanent magnet is further moved toward the tilted bronchus to move the cluster on the upper surface to the target bronchus.

[0102] In this embodiment, the microrobot cluster can be filled into a catheter, so that a bronchoscope can be used to quickly deploy the microrobot cluster from the outside to the main bronchus of the lung. In addition, the microrobot cluster can wrap imaging particles, and in the presence of mucus in the ex vivo pig lung, X-ray imaging technology can be used to track the cluster in real time, and external magnetic field guidance can be used to achieve targeted delivery.

[0103] In this embodiment, the microrobot cluster is used for deep targeted delivery in a target lung model or sample to perform imaging according to the delivery location. By setting up a microrobot cluster containing red fluorescent dye and imaging particles, the microrobot cluster can be successfully delivered to the deep target bronchus of the lung under computed tomography imaging, verifying the ability of the microrobot cluster to reconstruct on demand to avoid microgel particles from entering non-target bronchi and to accurately enter the oblique bronchi through climbing movements, such as Figure 6 As shown, Figure 6 Schematic diagram of the delivery of microrobot clusters in target pig lung samples under the guidance of computed tomography imaging. In addition, the fluorescent dye encapsulated by the microrobot clusters was also successfully delivered and released into the target bronchus.

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

[0105] Step S321, scanning the target lung using a computer tomography scanner, and performing bronchial three-dimensional structure reconstruction and delivery path planning;

[0106] Step S322, placing an endotracheal tube into the trachea of ​​the lung through the mouth, and inserting a bronchoscope into the main bronchus through the endotracheal tube;

[0107] Step S323, filling the micro-robot cluster into a catheter, inserting the catheter into the lumen of a bronchoscope, and delivering the micro-robot cluster to the main bronchus of the target lung;

[0108] Step S324, applying and moving the permanent magnet to guide the movement of the micro-robot cluster, and using the computed tomography to determine the position of the micro-robot cluster during the movement interval, and adjusting the position and angle of the permanent magnet;

[0109] Step S325, 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.

[0110] In one implementation of this embodiment, step S325 includes the following steps:

[0111] Step S325a, when encountering the downward bronchus, causing the permanent magnet to oscillate to change the shape of the micro-robot cluster and reduce the coverage area, so as to guide the micro-robot cluster to cross the downward bronchus;

[0112] Step S325b, when the microrobot cluster reaches the deep target bronchus, the microrobot cluster is fixed to the target bronchus using the permanent magnet and the wrapped cargo is released.

[0113] In this 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 the continuous secretion of mucus and the periodic expansion and contraction movement thereof, thereby simulating the continuous secretion of mucus and the periodic expansion and contraction movement of the pig lung in the pig body.

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

[0115] a. Preparation of microgel particles containing red fluorescent dye and developer particles.

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

[0117] c. Use a computed tomography scanner to scan the target lung and perform bronchial three-dimensional structure reconstruction and delivery path planning.

[0118] d. Place an endotracheal tube into the trachea through the mouth and insert a bronchoscope through the endotracheal tube into the mainstem bronchus.

[0119] e. Fill the cluster particles into a catheter and insert the catheter into the lumen of a bronchoscope to deliver the cluster to the main bronchus.

[0120] f. Apply and move the permanent magnet to guide the cluster movement, and use computed tomography to determine the cluster position during the movement gap, thereby adjusting the permanent magnet position and angle.

[0121] g. When encountering the downward bronchus, the permanent magnet is made to oscillate to change the shape of the cluster and reduce the coverage area of ​​the cluster, further guiding the cluster to cross the downward bronchus to ensure the integrity of the cluster.

[0122] h. After the cluster reaches the deep target bronchus, a permanent magnet is used to fix the cluster at the target location to release the encapsulated fluorescent dye.

[0123] In this embodiment, by simulating the continuous secretion of mucus by pig lungs in vivo and the periodic expansion and contraction movement, the microrobot cluster can move under the guidance of computed tomography imaging, and can perform shape reconstruction and wall climbing movements, successfully delivering the microrobot cluster to the deep target bronchus in the target lung and releasing the encapsulated cargo, thereby verifying the ability of the microrobot cluster to reconstruct on demand to avoid microgel particles from entering non-target bronchi and to accurately enter the inclined bronchi through climbing movements.

[0124] This embodiment adopts the above technical solution to achieve the following effects:

[0125] In this embodiment, microgel particles comprising magnetic particles, developing particles and cargo are prepared, and the prepared microgel particles are combined to obtain a microrobot cluster; and by controlling the movement, climbing and reconstruction of the microrobot cluster in a non-fluid environment, movement in a perforated pipe environment can be achieved; and by controlling the microrobot cluster to move in a lung sample under the guidance of X-rays, the microrobot cluster can be delivered to the target bronchus of the lung sample; or the microrobot cluster is controlled to deliver in the target lung under the guidance of computed tomography imaging, and the encapsulated cargo is released in the target bronchus; the microrobot cluster provided by the present invention can achieve targeted delivery in a lung environment filled with air, a lung environment with a mucus layer, and a target bronchus deep in the lung.

[0126] Exemplary Devices

[0127] like Figures 2 to 6 As shown, an embodiment of the present invention provides a micro-robot cluster for implementing the deep lung targeted delivery method described in the above embodiment, and the micro-robot cluster includes:

[0128] A microrobot cluster, wherein the microrobot cluster contains magnetic particles, imaging particles and microgel particles of cargo; the microrobot cluster is used for movement, climbing and reconstructing in a non-fluid environment to achieve movement in a perforated pipe environment; is used for moving in a lung sample under the guidance of X-rays and delivering 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 releasing the encapsulated cargo in the target bronchus.

[0129] In this embodiment, the micro-robot cluster is driven or used in conjunction with the following devices: a permanent magnet, used to control the movement direction and shape of the micro-robot cluster; an X-ray imaging device, used to use X-ray imaging to observe the bronchial distribution to determine the delivery path and permanent magnet driving mode; a computer tomography scanner, used to scan the target lungs, and perform bronchial three-dimensional structure reconstruction and delivery path planning; a bronchoscope, used to quickly deploy an external micro-robot cluster to the main bronchus.

[0130] In this embodiment, the formation, reconstruction, movement and delivery capabilities of the provided microrobot cluster that can be used for deep lung targeted delivery are centered on the design of microgel particles, the design and on-demand switching of the external driving magnetic field, and the combination with medical imaging modalities.

[0131] It can be understood that in this embodiment, the microrobot cluster can be used for movement, climbing and reconstructing in a non-fluid environment (for example, within a pipeline structure), thereby achieving movement in a perforated pipeline environment; it is also used to move in a lung sample under the guidance of X-rays and deliver cargo to the target bronchus of the lung sample; or to deliver in a target lung under the guidance of computed tomography imaging and release the encapsulated cargo in the target bronchus.

[0132] In this embodiment, before controlling the microrobot cluster as described above to perform deep lung targeted drug delivery, the microrobot cluster needs to be prepared.

[0133] Specifically, the microrobot cluster is composed of microgel particles, such as Figure 2 As shown, the microgel particles include: a hydrogel network, silica-wrapped magnetic microparticles, drugs and developer particles; wherein the developer particles can be prepared as needed; during the preparation process, the microgel particles in the microrobot cluster may only contain magnetic particles, the microgel particles in the microrobot cluster may also contain magnetic particles (i.e. developer particles), and the microgel particles in the microrobot cluster may also contain red fluorescent dyes and developer particles.

[0134] In this embodiment, the microgel particles contain magnetic particles and a large amount of water, which makes it possible to form clusters in a non-fluid environment. In addition, by using silica to wrap the magnetic particles, the biocompatibility of the formed microgel particles is ensured. The inclusion of magnetic particles allows the microgel particles to respond to the external magnetic field and causes the particles to be subjected to magnetic interactions from other particles. At the same time, since the microgel particles contain a large amount of water, liquid bridges exist between adjacent particles, causing the particles to be subjected to capillary forces and thus attract each other. Therefore, under an external rotating magnetic field, the microgel particles rotate in a non-fluid environment, contact with other particles and attract each other, forming a layered microrobot cluster.

[0135] The external driving magnetic field is used to achieve the movement and shape reconstruction of the microrobot cluster. By moving the external permanent magnet, the direction and magnitude of the magnetic gradient force applied to the microrobot cluster are changed, and the cluster can achieve translation, climbing and lifting movements in a tortuous and air-filled environment. By changing the angle of the permanent magnet so that its magnetization axis is perpendicular to the plane where the cluster is located, and adjusting the permanent magnet to oscillate at a preset frequency and oscillation angle, the vertical arrangement of the microgel particles is achieved, and the cluster shape is successfully transformed from a layered structure to a columnar structure.

[0136] The medical imaging modes include X-ray imaging and computed tomography imaging, which provide the possibility for the targeted delivery of microrobot clusters in ex vivo and in vivo pig lungs. Considering the air-filled environment in ex vivo and in vivo pig lungs, X-ray imaging and computed tomography imaging are used for cluster guidance. By wrapping the imaging particles into 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 movement, deformation and targeted delivery of the cluster in the ex vivo pig lung with a mucus layer and the pig lung with the characteristics of continuous secretion of mucus and lung contraction and expansion.

[0137] This embodiment adopts the above technical solution to achieve the following effects:

[0138] This embodiment proposes a microrobot cluster for deep lung targeted delivery, which can control the cluster to perform controllable movement and reversible shape reconstruction in a tortuous and air-filled environment and climb the wall under the action of an external rotating magnetic field and an oscillating magnetic field. By encapsulating the developing particles, the microrobot cluster can be positioned and tracked by medical imaging. Under X-ray guidance, the on-demand guidance of the microrobot cluster in an ex vivo pig lung with a mucus layer was achieved. Under computed tomography imaging, the microrobot cluster was successfully delivered to the deep target bronchus in the pig lung, verifying the cluster's ability to reconstruct on demand to avoid microgel particles from entering non-target bronchi, and to accurately enter the inclined bronchi through climbing movements. In addition, the fluorescent dye encapsulated by the microrobot cluster was also successfully delivered and released to the target bronchus.

[0139] Those skilled in the art can understand that all or part of the processes in the above-mentioned embodiments can be implemented by instructing related hardware through a computer program, and the computer program can be stored in a non-volatile storage medium. When the computer program is executed, it can include the processes of the embodiments of the above-mentioned methods. Among them, any reference to memory, storage, database or other media used in the embodiments provided by the present invention can include non-volatile and volatile memory.

[0140] In summary, the present invention provides a deep lung targeted delivery method and a microrobot cluster, the method comprising: preparing microgel particles comprising magnetic particles, developing particles and cargo, and combining the prepared microgel particles to obtain a microrobot cluster; controlling the movement, climbing and reconstruction of the microrobot cluster in a non-fluid environment to achieve movement in a perforated pipe environment; controlling the microrobot cluster to move in a lung sample under the guidance of X-rays, and delivering the microrobot cluster to the target bronchus of the lung sample; or controlling the microrobot cluster to deliver in the target lung under the guidance of computed tomography imaging, and releasing the wrapped cargo in the target bronchus; the microrobot cluster provided by the present invention can achieve targeted delivery in a lung environment filled with air, a lung environment with a mucus layer, and a target bronchus deep in the lung.

[0141] It should be understood that the application of the present invention is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A method for deep lung targeted delivery, characterized in that: The deep lung targeted delivery method comprises: preparing microgel particles comprising magnetic particles, developing particles and cargo, and combining the prepared microgel particles to obtain a microrobot cluster; Controlling the movement, climbing and reconstruction of the micro-robot cluster in a non-fluid environment to achieve movement in a perforated pipe environment; Control the microrobot cluster to move in the lung sample under the guidance of X-rays, and deliver the microrobot cluster to the target bronchus of the lung sample; or control the microrobot cluster to deliver in the target lung under the guidance of computed tomography imaging, and release the encapsulated cargo in the target bronchus.

2. The deep lung targeted delivery method according to claim 1, characterized in that: The controlling the movement, climbing and reconstruction of the micro-robot cluster in a non-fluid environment to achieve movement in a perforated pipe environment includes: placing the microrobot cluster on a platform above a permanent magnet; Controlling the permanent magnet to perform rotation and translation motion, changing 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 translation motion; When the micro-robot cluster moves in the pipeline structure, the rotating permanent magnet is slowly moved around the outer surface of the pipeline to make the micro-robot cluster climb the wall; Adjusting the angle of the permanent magnet and performing an oscillating motion to cause particles in the microrobot cluster to gather in a vertical direction, thereby transforming the shape of the microrobot cluster into a columnar structure; When the micro-robot cluster is in the columnar structure, the micro-robot cluster is controlled to move in a pipe environment with holes by slowly moving the permanent magnet.

3. The deep lung targeted delivery method according to claim 2, characterized in that: The adjusting the angle of the permanent magnet and performing an oscillating motion to make the particles in the micro-robot cluster gather in a vertical direction and transform the shape of the micro-robot cluster into a columnar structure includes: The angle of the permanent magnet is adjusted so that the magnetization axis of the permanent magnet is perpendicular to the plane where the micro-robot cluster is located, and an oscillating motion is performed to transform the micro-robot cluster from a planar structure to a columnar structure and reduce the coverage area of ​​the micro-robot cluster.

4. The method for deep lung targeted delivery according to claim 2, characterized in that: The step of controlling the microrobot cluster to move in the lung sample under the guidance of X-rays and delivering the microrobot cluster to the target bronchus of the lung sample comprises: placing the lung sample under an X-ray imaging device; Using X-ray imaging to observe the bronchial distribution of the lung sample, determine the delivery path and permanent magnet driving mode; Filling the microrobot cluster into a catheter, placing the catheter in the lumen of a bronchoscope, and deploying the microrobot cluster to the main bronchus; The bronchoscope is removed, a rotating permanent magnet is applied, and the permanent magnet is slowly moved along a predetermined path to guide the movement of the micro-robot cluster; According to the target bronchus type of the lung sample, the micro-robot cluster is guided to move from the entrance of the descending bronchus, or the micro-robot cluster is moved from the bottom surface to the upper surface until it moves to the target bronchus.

5. The method for deep lung targeted delivery according to claim 4, characterized in that: The step of guiding the microrobot cluster to move from the entrance of the descending bronchus according to the target bronchus type of the lung sample comprises: When encountering a downward bronchus, the permanent magnet driving mode is switched to an oscillation mode, the shape of the micro-robot cluster is changed to reduce the cluster coverage area, and the micro-robot cluster is guided to move beside the entrance of the downward bronchus.

6. The method for deep lung targeted delivery according to claim 4, characterized in that: The step of moving the micro-robot cluster from the bottom surface to the upper surface until it reaches the target bronchus comprises: When the upwardly tilted bronchus is the target bronchus, a rotating permanent magnet is placed above the micro-robot cluster to move the micro-robot cluster from the bottom surface to the upper surface until it moves to the target bronchus.

7. The method for deep lung targeted delivery according to claim 2, characterized in that: The method of controlling the microrobot cluster to deliver in the target lung under the guidance of computed tomography imaging and releasing the encapsulated cargo in the target bronchus comprises: Scanning the target lung using a computer tomography scanner, and performing bronchial three-dimensional structure reconstruction and delivery path planning; An endotracheal tube is placed through the mouth into the trachea of ​​the lung, and a bronchoscope is inserted through the endotracheal tube into the mainstem bronchus; Filling the microrobot cluster into a catheter, inserting the catheter into the lumen of a bronchoscope, and delivering the microrobot cluster to the main bronchus of the target lung; Applying and moving the permanent magnet to guide the movement of the micro-robot cluster, and using the computed tomography to determine the position of the micro-robot cluster during the movement interval, and adjusting the position and angle of the permanent magnet; According to the position of the micro-robot cluster, the driving mode of the permanent magnet is adjusted to control the micro-robot cluster to release the wrapped cargo in the target bronchus.

8. The method for deep lung targeted delivery according to claim 7, characterized in that: The method of 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: When encountering the downward bronchus, the permanent magnet is made to oscillate to change the shape of the micro-robot cluster and reduce the coverage area, so as to guide the micro-robot cluster to cross the downward bronchus; When the microrobot cluster reaches the deep target bronchus, the microrobot cluster is fixed to the target bronchus using the permanent magnet and the encapsulated cargo is released.

9. A micro-robot cluster for implementing the deep lung targeted delivery method according to any one of claims 1 to 8, characterized in that: The micro robot cluster comprises: A microrobot cluster, wherein the microrobot cluster contains magnetic particles, imaging particles and microgel particles of cargo; the microrobot cluster is used for movement, climbing and reconstructing in a non-fluid environment to achieve movement in a perforated pipe environment; is used for moving in a lung sample under the guidance of X-rays and delivering 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 releasing the encapsulated cargo in the target bronchus.

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