Food-grade micro-robot
Through the synergistic design of magnetic drive and ultrasound power supply, magnetic navigation and reversible anchoring of the gastrointestinal microrobot were achieved, solving the problems of uncontrollable drug release and unstable adhesion, improving drug delivery efficiency and treatment precision, especially with significant effects in multi-point treatment within the gastrointestinal tract.
Patent Information
- Application Number
- CN202512002545.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-29
- Publication Date
- 2026-03-06
Smart Images
Figure CN121606802A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of microrobots mediating ionic drug efficacy and their local drug delivery technology in the gastrointestinal tract, and more specifically, to a food-grade microrobot. Background Technology
[0002] Systemic drug delivery struggles to achieve high spatial and temporal focus simultaneously, with drug deposition rates at tumor sites typically below 1% and extremely low penetration efficiency. While existing gastrointestinal microrobots can achieve active navigation, they suffer from the following drawbacks: 1) Drug release relies on passive diffusion, which is inefficient and cannot be precisely controlled; 2) Adhesive structures are prone to detachment or difficult to detach, hindering multi-point treatment; 3) They lack targeted anti-tumor mechanisms, resulting in limited efficacy. The gastrointestinal tract, however, possesses natural oral accessibility, and copper ions (Cu²⁺) can trigger the "cuproptosis" pathway, exhibiting significant lethal effects on various digestive tract tumor cells. Therefore, this invention addresses the core pain points of existing microrobots—uncontrollable release, unstable anchoring, and low transmission efficiency—through a synergistic design of "magnetically driven navigation + reversible anchoring + ultrasound-powered electrochemical copper release." Summary of the Invention
[0003] To overcome the shortcomings of existing technologies, this invention provides an edible microrobot, more specifically, an edible microrobot that can be orally delivered, positioned and anchored, and electrochemically release copper under the power of external focused ultrasound, thereby enabling temporal and climatic control of Cu²⁺ pharmacokinetics in the tumor periphery. This robot achieves long-distance rolling navigation through magnetic actuation, reversible anchoring through biomimetic micro-spiky adhesive pads, and uses focused ultrasound (FUS) as the energy input to drive an on-chip piezoelectric transducer to generate an adjustable potential, forming a three-dimensional electric field between multi-electrode copper electrodes. This triggers rapid transport dominated by electrochemical dissolution and electromigration of solid copper, significantly improving local pharmacokinetics.
[0004] The technical solution adopted by this invention to solve its technical problem is:
[0005] An edible microrobot includes a magnetically responsive skeleton, at least two pairs of spatially distributed solid copper electrodes, a piezoelectric transducer and its driving circuit, a bioadhesive pad, and an external magnetic field response unit for attitude and trajectory control.
[0006] The magnetic response skeleton is used to achieve rolling navigation and attitude adjustment within the gastrointestinal tract.
[0007] The piezoelectric transducer is configured to output a potential under external focused ultrasonic excitation;
[0008] The surface of the bioadhesive pad has a micro-spiky structure to achieve reversible adhesion to a wet mucus layer;
[0009] The piezoelectric transducer forms an electric field with the solid copper electrode under focused ultrasound power, which drives the electrochemical dissolution of copper in physiological fluid and generates a local high concentration of copper ions, thereby enabling spatiotemporal controllable regulation of Cu²⁺ pharmacokinetics in the tumor periphery.
[0010] Furthermore, the bioadhesive pad is a chitosan-containing microspinous adhesive structure with a microspin height of 20 to 150 μm and a density of 10 to 40 per square millimeter. The adhesion force at the target site is 2 to 5 mN. This adhesion force ensures that the robot is stably anchored in the gastrointestinal peristalsis environment and can be desorbed under the action of a reverse magnetic field of not less than 50 mT.
[0011] Furthermore, the copper electrode adopts a four-legged symmetrically arranged electric multipole structure to expand the effective treatment coverage area and form a basically annular ion cloud front.
[0012] Furthermore, the ultrasonic operating frequency of the piezoelectric transducer is 100 to 1000 kHz, and the applied sound pressure is 10 to 50 kPa.
[0013] Furthermore, the magnetically responsive framework material is a mixed magnetic 3D printing photosensitive resin containing micron-sized neodymium iron boron and nano-sized Fe3O4, with the neodymium iron boron particle size ranging from 5 to 20 μm. The particle size is 5 to 20 nm and the total solid content is 10% to 20%.
[0014] Furthermore, the oligomers of the photosensitive resin include polycyclic aliphatic acrylates and polyurethane acrylates, and the photoinitiator is acryloylcarboxylic acid diester, with a mass ratio of 50:1 to 65:1.
[0015] Furthermore, the microrobot is encapsulated in an edible capsule for oral administration, and the capsule dissolves in gastric juice within 5 to 20 minutes to release the microrobot.
[0016] Furthermore, under the condition that the electrode spacing of the solid copper electrode is 1 to 3 mm and the output potential is about 3.0 V, the microrobot forms copper ion transport dominated by electromigration and obtains an effective transport efficiency that is at least two orders of magnitude higher than that of molecular diffusion.
[0017] Furthermore, the geometry and spacing of the solid copper electrodes are selected to achieve EC under standard operating conditions. 90 A copper ion cloud-covered region characterized by frontal closure.
[0018] Furthermore, the electrode spacing of the solid copper electrode is 0.3 to 5 mm; the piezoelectric transducer is configured to output a potential of 1.4 to 3.0 V under external focused ultrasonic excitation;
[0019] The beneficial effects of this food-grade microrobot are:
[0020] Highly efficient delivery: Compared with drug release methods that rely on molecular diffusion in existing technologies, this invention forms Cu²⁺ ion clouds dominated by electromigration under conditions of Φ≈1.4–3V and electrode spacing of about 1–3mm. The effective diffusion coefficient Deff is improved by at least two orders of magnitude compared with ordinary diffusion, which can quickly achieve Cu²⁺ saturation in deep tumor tissue.
[0021] Precision treatment: Through the synergy of magnetically driven navigation and reversible adhesive pads, it can be located and anchored in multiple segments of the gastrointestinal tract and can be detached under the action of a reverse magnetic field, enabling continuous treatment of multiple microlesions. Attached Figure Description
[0022] The present invention will now be described in further detail with reference to the accompanying drawings and specific implementation methods.
[0023] Figure 1 This diagram illustrates the overall structure of the microrobot of the present invention and the delivery of the oral capsule.
[0024] Figure 2 This is a schematic diagram of magnetic drive navigation, rolling motion, and reversible anchoring mechanisms.
[0025] Figure 3 A schematic diagram of the ultrasonic power supply—piezoelectric output—electric multipole field—electrochemical copper release link.
[0026] Figure 4 For Cu²⁺ ion cloud distribution and EC 90 Frontier and Coverage Area S t A diagram illustrating the definition.
[0027] Figure 5 This figure shows the results of in vitro experiments using monolayer cells and spherical tumor models.
[0028] Figure 6 This is a diagram of navigation and long-term anchoring experiments in an isolated porcine gastrointestinal model.
[0029] Figure 7 This is a schematic diagram illustrating the antitumor effect and histological verification in animals. Detailed Implementation
[0030] like Figure 1 As shown, an edible microrobot includes a magnetically responsive skeleton, at least two pairs of spatially distributed solid copper electrodes, a piezoelectric transducer and its driving circuit, a bio-adhesive pad, and an external magnetic field response unit for attitude and trajectory control.
[0031] like Figure 2 As shown, the magnetic response skeleton is used to realize rolling navigation and attitude adjustment within the gastrointestinal cavity;
[0032] like Figure 3 As shown, the piezoelectric transducer is configured to output a potential under external focused ultrasonic excitation;
[0033] The surface of the bioadhesive pad has a micro-spiky structure to achieve reversible adhesion to a wet mucus layer;
[0034] like Figure 3 As shown, the piezoelectric transducer forms an electric field between itself and the solid copper electrode under focused ultrasound power, thereby driving the electrochemical dissolution of copper in physiological fluid and generating a local high concentration of copper ions, thus enabling spatiotemporal controllable regulation of Cu²⁺ pharmacokinetics in the tumor periphery.
[0035] like Figure 6 As shown, the bioadhesive pad is a chitosan-containing microspinous adhesive structure with a microspin height of 20 to 150 μm and a density of 10 to 40 per square millimeter. The adhesion force at the target site is 2 to 5 mN. This adhesion force ensures that the robot is stably anchored in the gastrointestinal peristalsis environment and can be desorbed under the action of a reverse magnetic field of not less than 50 mT.
[0036] like Figure 3 As shown, the copper electrode adopts a four-legged symmetrically arranged electric multipole structure to expand the effective treatment coverage area and form a basically annular ion cloud front.
[0037] The ultrasonic operating frequency of the piezoelectric transducer is 100 to 1000 kHz, and the applied sound pressure is 10 to 50 kPa.
[0038] The magnetic response framework material contains micron-sized neodymium iron boron and nano-sized... The mixed magnetic 3D printing photosensitive resin has a neodymium iron boron particle size of 5 to 20 μm, an Fe3O4 particle size of 5 to 20 nm, and a total solid content of 10% to 20%.
[0039] The oligomers of the photosensitive resin include polycyclic aliphatic acrylates and polyurethane acrylates, and the photoinitiator is acryloylcarboxylic acid diester, with a mass ratio of 50:1 to 65:1.
[0040] like Figure 1 As shown, the microrobot is encapsulated in an edible capsule for oral administration, and the capsule dissolves in gastric juice within 5 to 20 minutes to release the microrobot.
[0041] With a solid copper electrode spacing of 1 to 3 mm and an output potential of approximately 3.0 V, the microrobot achieves copper ion transport dominated by electromigration and obtains an effective transport efficiency that is at least two orders of magnitude higher than that of molecular diffusion.
[0042] like Figure 4As shown, the geometry and spacing of the solid copper electrodes are selected to achieve EC under standard operating conditions. 90 A copper ion cloud-covered region characterized by frontal closure.
[0043] The solid copper electrodes have an electrode spacing of 0.3 to 5 mm; the piezoelectric transducer is configured to output a potential of 1.4 to 3.0 V under external focused ultrasonic excitation;
[0044] The structure and materials of this invention: The microrobot of this invention includes: a magnetically responsive skeleton, at least two pairs of spatially distributed solid copper electrodes, a piezoelectric transducer and its driving circuit, a bio-adhesive pad, and an external magnetic field response unit for attitude and trajectory control. The magnetically responsive skeleton is used to achieve rolling and flipping, and the bio-adhesive pad is composed of an array of micro-spiky structures with chitosan adhesion properties (spiky height and density can be optimized according to tissue conditions) for reversible anchoring on the mucus layer.
[0045] The kinetics and power supply of this invention: such as Figure 2 As shown, an external changing magnetic field is used to achieve remote rolling and attitude control of the robot within cavities such as the stomach, small intestine, and colon; focused ultrasound (FUS) is used to drive an on-chip piezoelectric transducer, enabling it to output an adjustable potential Φ (approximately 1.4) between copper electrodes. (3V), forming a three-dimensional electric multipole field, driving the electrochemical dissolution of Cu→Cu²⁺.
[0046] The pharmacokinetic regulation mechanism of this invention is as follows: Under the conditions of Φ≈3V and characteristic length d≈1mm, the Péclet number Pe is much greater than 10, and electromigration becomes the dominant factor. Effective diffusion coefficient It achieves an improvement of approximately 10² times compared to conventional diffusion; through the design of electrode geometry and spacing, it enables... cutting edge( ) and effective treatment coverage area To achieve the target threshold, rapid saturation and destruction of deep tissues are accomplished. The local Cu²⁺ concentration threshold at which the predetermined pharmacological effect is achieved is 90%, which is the effective concentration required to achieve a 90% inhibitory / killing effect. This refers to the situation where, with the copper-releasing electrode (or the geometric center of the electrode) as a reference, the local Cu²⁺ concentration is exactly equal to... The minimum distance from the spatial position corresponding to the time to the reference point can be understood as " The characteristic radius of the isoconcentration surface or the critical ion cloud front; Refer to The projected area of the region on the surface or characteristic section of the target tissue reflects, under the current ultrasound parameters and magnetic field sequence, that the local Cu²⁺ concentration is not less than [amount missing]. (Effective treatment coverage area)
[0047] This invention relates to oral delivery and anchoring: the robot is encapsulated in an edible gelatin capsule, which dissolves and releases approximately 15 minutes after entering the stomach cavity; driven by an alternating magnetic field, it traverses multiple segments of the gastrointestinal tract, and upon reaching the target, it utilizes micro-spiky adhesion to achieve an adhesion force on the order of approximately mN, and can achieve rapid desorption under a reverse magnetic field of ≥50mT.
[0048] Embodiments of the present invention: 1) Monolayer cell and tumor sphere model, such as Figure 5 As shown: In spherical tumor models with diameters of 0.3–2.5 mm, a single treatment for 6 hours can yield [results]. A 90% cell death rate and significant tissue structural disintegration were observed. (For example, in an HT-29 spherical tumor model with a diameter of approximately 1.3 mm, a single 6-hour treatment using the local copper release system based on external field power supply and electromigration of this invention resulted in an overall cell death rate greater than 90%, and significant disintegration of the overall tumor spheroid structure. In contrast, under the same treatment time, the traditional Cu wire-powered group or the unpowered control group only showed superficial focal necrosis, with an overall cell death rate far below 90%, and the main structure of the tumor spheroid remained largely intact. These results demonstrate that the system of this invention can achieve rapid saturation and efficient killing of deep tissues within a short treatment course in millimeter-scale solid tumor models, exhibiting significant therapeutic advantages.)
[0049] 2) Ex vivo tissue: Under continuous FUS conditions (e.g., 500kHz, 20kPa), the robot maintains long-term anchoring and stable copper release; 3) Animal experiments, such as... Figure 7 As shown: In the HT-29 xenograft mouse model, a single 6-hour treatment resulted in a significant decrease in tumor volume, and TUNEL and cuprottosis-related proteins (such as FDX1, LIAS, SDHB, and DLAT) exhibited changes consistent with the pathway.
[0050] Optional implementations of this invention include: optimization of electrode geometry (e.g., quadrupedal symmetry) and spacing; tissue adaptation of microneedle size and density; closed-loop control combined with imaging or electrical impedance feedback; multi-point sequential treatment and robot retrieval.
[0051] The invention has industrial applicability: the device structure and operating parameter window are clearly defined, and it can be realized through mature microelectromechanical processing and focused ultrasound equipment, making it suitable for preclinical research and future device transformation.
[0052] Figure 1 The invention illustrates a food-grade local copper release device for regulating the pharmacokinetics of copper ions in gastrointestinal tumors and its typical operating scenario within the gastrointestinal tract.
[0053] Structurally, the device shown in the figure includes: a soft magnetic composite skeleton, a built-in piezoelectric transducer and its driving circuit, multi-pole solid copper electrodes arranged at the ends of the device's four limbs, and a biomimetic micro-spiky bioadhesive pad covering the surface of the device.
[0054] From the perspective of external field coupling, the figure illustrates that the external magnetic field generating device applies an alternating / rotating magnetic field and magnetic field gradient to the device to achieve rolling, turning and positioning along the surface of the gastrointestinal mucosa; the external focused ultrasound power supply module excites the piezoelectric transducer inside the device through external irradiation, so that it outputs an adjustable potential between the copper electrodes, forming a three-dimensional electric multipole field and triggering electrochemical copper release.
[0055] In terms of application scenarios, the figure shows the process of the device being delivered orally to the stomach cavity via an edible capsule. After the capsule dissolves and releases the device, it approaches and anchors to the surface of a tumor in the gastrointestinal tract under the drive of a magnetic field, and forms a local Cu²⁺ ion cloud near the lesion under the power of focused ultrasound.
[0056] Figure 2 The mechanism of navigation, rolling motion, and reversible anchoring on the gastrointestinal mucosa surface of a controlled object under the influence of an external magnetic field is shown.
[0057] Part of the diagram illustrates how, driven by a uniform rotating magnetic field, a soft magnetic skeleton periodically flips or rolls around its own center of gravity. The device moves directionally along the mucosal surface, bypassing complex morphologies such as folds and wrinkles, enabling cross-segmental navigation from the stomach to the small intestine and then to the colon.
[0058] Another part illustrates that when a magnetic field with a gradient component is applied, the device can accelerate towards the mucosal surface on the side with higher magnetic field strength, and generate an adhesive force on the order of mN under the action of the biomimetic micro-spur adhesive pad, thereby achieving anchoring of the target area.
[0059] It also illustrates that when the direction or intensity of the applied magnetic field changes, the force state at the adhesive pad changes, the adhesive force drops below the threshold, and the device can achieve rapid detachment, thereby completing the transfer from one lesion point to the next.
[0060] Figure 3 This invention illustrates the coupling relationship between the external focused ultrasound power supply and the internal piezoelectric transducer and electrode structure, as well as the resulting Cu²⁺ ion source mechanism.
[0061] The upper or left side of the diagram illustrates an external focused ultrasound transducer that emits focused ultrasound waves of a certain frequency and intensity (e.g., 500 kHz, approximately 20 kPa) on the body surface or outside of a cavity. The energy is coupled to the piezoelectric transducer inside the device within the focusing area.
[0062] The middle section illustrates how a piezoelectric transducer converts acoustic energy into electrical energy, outputting a potential difference (e.g., Φ≈1.4–3V) with a certain amplitude and duty cycle between relatively arranged multi-electrode copper electrodes, forming a local strong electric field in the tissue and stroma space adjacent to the tumor surface.
[0063] The lower or right side illustrates that under the action of this electric field, the copper electrode undergoes an anodic electrochemical reaction to generate Cu²⁺ ions, which, under the combined action of electromigration and diffusion, form an ion cloud pointing towards the tumor tissue, thus providing a physical basis for subsequent reaction-drift-diffusion modeling and parameter design.
[0064] Figure 4 The spatial distribution of Cu²⁺ ion clouds and EC₂ during local copper release are shown. 90 Frontier location and effective coverage area S t The definition method.
[0065] The figure shows the Cu²⁺ concentration field distribution in the surrounding space at different times or under different operating conditions, with the geometric center of the electrode as a reference. The line marked in the isoconcentration line is the "effective efficacy front", and its distance from the electrode center is defined as...
[0066] The diagram illustrates how the area on the tumor surface or a specific cross-section is projected onto a plane, and the resulting area is used to characterize the size of the "high-efficiency treatment area" under the current energy supply and field parameters.
[0067] Furthermore, the figure may also indicate, through curves or schematic arrows, that as the external field parameters, electrode spacing, or power supply time change, and S... t This will increase or decrease accordingly, thus providing a direct basis for the controller to adjust the treatment time and coverage using Pe.
[0068] Figure 5 The results of in vitro local copper release experiments using the system of the present invention in monolayer tumor cells and spherical tumor models are shown, illustrating the killing effect of locally efficient Cu²⁺ ion clouds on tumor cells.
[0069] The data / images in the figure show the live / dead staining results and survival rate statistics of monolayer tumor cells under different treatment conditions. By comparing the local copper release conditions of the present invention with the homogenized solution administration conditions, it can be seen that the present invention achieves a higher cell mortality rate at the same or lower total dose.
[0070] Another set of images shows the structural changes of spherical tumor models (tumor spheres) with diameters ranging from approximately 0.3 to 2.5 mm after a single local copper release treatment of approximately 6 hours: it can be seen that obvious cell death and structural disintegration occur from the surface to the deep layers of the tumor spheres, with an overall mortality rate of more than 90%, while the control group or the traditional energy supply group mostly only has limited necrosis on the surface, and the main structure of the sphere remains basically intact.
[0071] This figure is used to demonstrate that the present invention can still achieve highly efficient killing of deep tissues in a single short treatment in a millimeter-scale three-dimensional tumor model with a certain diffusion barrier, which is superior to the traditional passive diffusion drug delivery method.
[0072] Figure 6 The experimental results show the verification of magnetic navigation, cross-segment movement, and long-term anchoring stability of the controlled object in an isolated pig stomach and intestinal segment model.
[0073] The figure first shows the trajectory and speed of the device on the isolated gastric mucosa, illustrating that under the drive of an external rotating magnetic field, the device can roll stably along the tortuous mucosal surface and bypass the folded structure without slipping or getting stuck.
[0074] The device was then shown in a diagram illustrating its cross-segmental movement from the stomach segment into the small intestine segment and then into the colon segment, demonstrating that the system can complete long-distance navigation under realistic size and friction conditions.
[0075] Another set of images or curves shows the time the device remains anchored on the mucosal surface under continuous focused ultrasound power and a continuous magnetic field. The images show that the device position does not drift or fall off for tens of minutes or even longer, verifying the long-term stability of the biomimetic micro-spiky adhesive pad in the gastrointestinal tract.
Claims
1. An edible micro-robot, characterized by, The micro-robot comprises a magnetic responsive skeleton, at least two pairs of spatially distributed solid copper electrodes, a piezoelectric transducer and its driving circuit, a bioadhesive pad, and an external magnetic field responsive unit for attitude and trajectory control. The magnetic responsive skeleton is used to achieve rolling navigation and attitude adjustment in the gastrointestinal tract cavity. The piezoelectric transducer is configured to output an electric potential under external focused ultrasound excitation. The bioadhesive pad has a microspine structure on its surface to achieve reversible adhesion on a wet mucus layer. The piezoelectric transducer forms an electric field between the solid copper electrodes under focused ultrasound power supply to drive electrochemical dissolution of copper in physiological fluid and generate a local high concentration of copper ions, thereby achieving spatiotemporal controllable regulation of tumor periregional Cu²⁺ pharmacokinetics.
2. The food-grade microrobot according to claim 1, wherein: The bioadhesive pad is a chitosan-containing microspine adhesive structure with a microspine height of 20 to 150 μm, a density of 10 to 40 per square millimeter, and an adhesion force of 2 to 5 mN at the target site, which ensures stable anchoring of the robot in the gastrointestinal tract peristalsis environment and detachment under the action of a reverse magnetic field of not less than 50 mT.
3. An edible micro-robot according to claim 2, wherein: The copper electrodes adopt an electric multipole structure with a four-legged symmetrical arrangement to expand the effective treatment coverage area and form a substantially annular ion cloud front.
4. The food-grade microrobot according to claim 3, wherein: The ultrasonic operating frequency of the piezoelectric transducer is 100 to 1000 kHz, and the acting sound pressure is 10 to 50 kPa.
5. An edible micro-robot according to claim 4, wherein: The magnetic responsive framework material is a mixed magnetic 3D printing photosensitive resin containing micron-sized neodymium iron boron and nanometer-sized Neodymium iron boron particle size is 5 to 20 μm, The diameter is 5 to 20 nm, and the total solid content is 10% to 20%.
6. An edible micro-robot according to claim 5, wherein: The oligomer of the photosensitive resin comprises polycyclic aliphatic acrylate and polyurethane acrylate, and the photoinitiator is acryloyl carboxylic diester with a mass ratio of 50:1 to 65:
1.
7. An edible micro-robot according to claim 6, wherein: The micro-robot is encapsulated in an edible capsule to achieve oral administration, and the capsule dissolves to release the micro-robot in gastric juice within 5 to 20 minutes.
8. An edible micro-robot according to claim 7, wherein: Under the conditions that the electrode spacing of the solid copper electrode is 1 to 3 mm and the output potential is about 3.0 V, the micro-robot forms copper ion transmission dominated by electrotransport and obtains an effective transmission efficiency improved by at least two orders of magnitude relative to molecular diffusion.
9. An edible micro-robot according to claim 8, wherein: The solid copper electrode geometry and spacing are chosen to obtain an EC 90 The copper ion cloud coverage area is characterized by a leading edge closure.
10. The food-grade microrobot according to claim 9, wherein: The electrode spacing of the solid copper electrode is 0.3 to 5 mm; and the piezoelectric transducer is configured to output an electric potential of 1.4 to 3.0 V under external focused ultrasound excitation.