Focused ultrasound stimulation system for modulating liver metabolism and control method

Abstract

The application discloses a focused ultrasound stimulation system and a control method for regulating liver metabolism, and the system comprises a focused ultrasound transducer, a robot positioning module, an image navigation module and a control module. The image navigation module acquires an ultrasound image of a target region, identifies feature points of a hepatic portal region and generates target point coordinates. The robot positioning module carries and moves the focused ultrasound transducer. The control module controls the robot positioning module to dynamically move the focused ultrasound transducer according to the real-time updated target point coordinates, so that the focal domain of the focused ultrasound transducer coincides with the target region, and controls the focused ultrasound transducer to output low-intensity focused ultrasound. The application also provides application of low-intensity focused ultrasound in preparation of a device for treating non-alcoholic fatty liver disease. The system realizes non-invasive physical regulation of liver metabolism, effectively improves lipid deposition and inflammation state, and has the advantages of automation, precision and repeatability.

Description

Technical Field

[0001] This invention relates to the field of biomedical engineering technology, and in particular to a focused ultrasound stimulation system and control method for regulating liver metabolism. Background Technology

[0002] Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by abnormal lipid deposition in the liver. Its development is closely related to hepatic lipid metabolism disorders and chronic inflammatory responses. Currently, the main treatments for NAFLD are lifestyle interventions and drug therapy. However, drug therapy has limitations, including limited efficacy, significant side effects, and poor long-term adherence. Therefore, exploring new treatment methods is of great importance.

[0003] In recent years, focused ultrasound (FUS), as a non-invasive physical stimulation technique, has shown potential value in neuromodulation and intervention for metabolic diseases. However, existing FUS-based modulation techniques mainly suffer from the following technical limitations: First, existing research mainly focuses on ultrasound modulation mechanisms mediated by the vagus nerve. Such research often relies on nerve transection, invasive procedures, or complex neuromodulation conditions, which not only increases the complexity of the procedure and the risk of trauma, but also limits its clinical application.

[0004] Second, existing focused ultrasound systems lack the ability to precisely target the local microenvironment of the liver. Traditional ultrasound stimulation usually uses a wide-area irradiation method, which makes it difficult to achieve precise overlap between the focal zone and specific liver anatomical structures (such as the porta hepatis), resulting in low energy delivery efficiency, large individual differences, and affecting the stability and repeatability of treatment effects.

[0005] Third, the existing technical solutions lack a systematic basis for optimizing the setting of ultrasound parameters. Different studies use different parameters, and a set of quantifiable and repeatable parameter combinations has not been formed, making it difficult to verify and promote the treatment effect.

[0006] Fourth, most existing focused ultrasound systems use manual positioning, which relies on the operator's experience. The positioning accuracy and consistency are difficult to guarantee, and it is impossible to achieve automated and standardized treatment procedures.

[0007] Therefore, there is an urgent need for a focused ultrasound stimulation system that can precisely target the hepatic hilum region, has controllable parameters, and does not require nerve transection. This system can directly act on the local microenvironment of the liver through physical stimulation, regulate liver metabolism and inflammatory response, and thus achieve effective intervention for non-alcoholic fatty liver disease. Summary of the Invention

[0008] In view of this, the purpose of the present invention is to provide a focused ultrasound stimulation system and control method for regulating liver metabolism. The system integrates image navigation and robot positioning into a focused ultrasound stimulation system, which accurately targets the porta hepatis region to output low-intensity focused ultrasound, thus solving the technical problem that the prior art cannot accurately regulate liver lipid metabolism and inflammatory response in a non-invasive and repeatable manner.

[0009] To achieve the above objectives, the present invention provides the following technical solution: The focused ultrasound stimulation system for regulating liver metabolism provided by the present invention includes a focused ultrasound transducer, a robot positioning module, an image navigation module, and a control module; The focused ultrasound transducer is used to generate and emit focused ultrasound, including low-intensity focused ultrasound and high-intensity focused ultrasound. The robot positioning module is used to carry and move the focused ultrasound transducer. The robot positioning module includes a multi-degree-of-freedom robotic arm, and the focused ultrasound transducer is fixedly installed at the end of the multi-degree-of-freedom robotic arm. The image navigation module is used to acquire ultrasound images of the target area and identify feature points in the hepatic hilum region based on the ultrasound images to generate target point coordinates. The porta hepatis region includes the anatomical area where the hepatic artery, portal vein, and bile duct converge; the image navigation module includes an ultrasound probe and an image processing unit, the image processing unit being used to identify the convergence features of the hepatic artery, portal vein, and bile duct in the porta hepatis region and to calculate the target coordinates; The control module is connected to the focused ultrasound transducer, the robot positioning module, and the image navigation module, respectively, and the control module is configured as follows: The image navigation module is controlled to acquire ultrasound images of the porta hepatis region in real time, identify feature points in the porta hepatis region, dynamically generate target coordinates, and update the target coordinates in real time according to the displacement of the porta hepatis region caused by respiratory movements. Based on the target coordinates updated in real time, the robot positioning module is controlled to dynamically move the focused ultrasound transducer so that the focal area of ​​the focused ultrasound transducer coincides with the hepatic hilum region at various times during the respiratory cycle. The focused ultrasound transducer is controlled to output low-intensity focused ultrasound according to a first preset parameter to provide non-invasive stimulation to the porta hepatis region; and The focused ultrasound transducer is controlled to output high-intensity focused ultrasound according to the second preset parameters in order to ablate the tissue in the porta hepatis region.

[0010] Furthermore, the low-intensity focused ultrasound output by the first preset parameter can cause at least one of the following changes in the target liver tissue: It reduces liver triglyceride levels, lowers serum transaminase levels, increases serum high-density lipoprotein levels, lowers serum low-density lipoprotein levels, lowers serum total cholesterol levels, lowers serum triglyceride levels, lowers fasting blood glucose levels, lowers glycated hemoglobin levels, and reduces the expression levels of liver inflammatory factors TNF-α and IL-1β.

[0011] Furthermore, the image navigation module is used to plan target points and establish a coordinate system before treatment, to monitor the focal zone position and target point offset in real time during treatment, and to confirm the target area coverage after treatment.

[0012] Furthermore, the image processing unit includes a coordinate calibration subunit, which is used to establish the spatial transformation relationship between the image coordinate system of the ultrasonic probe and the mechanical coordinate system of the robot positioning module.

[0013] Furthermore, the robot positioning module includes a servo driver, which drives the multi-degree-of-freedom robotic arm to move according to the instructions of the control module.

[0014] Furthermore, when the focused ultrasound transducer emits low-intensity ultrasound for modulation, its center frequency is 0.5MHz-2.0MHz, peak negative pressure is 0.5MPa-3.0MPa, pulse wave, and duty cycle is 0.01%-0.5%. When the focused ultrasound transducer emits high-intensity ultrasound for ablation, its center frequency is 0.5 MHz-2.0 MHz, the peak negative pressure is 3.0 MPa-10.0 MPa, and it is a continuous wave or a pulse wave with a duty cycle greater than 50%.

[0015] Furthermore, the focused ultrasound transducer is a phased array transducer, and the control module is also configured to achieve electronic focusing on the hepatic hilum region by adjusting the excitation signal delay of each element of the phased array transducer.

[0016] Furthermore, it also includes a constant temperature water bath module connected to the control module, used to contain degassed water and maintain a preset water temperature, wherein the focused ultrasonic transducer and the target area are immersed in the degassed water.

[0017] The present invention relates to the application of low-intensity focused ultrasound in the preparation of a device for treating non-alcoholic fatty liver disease, wherein the device is the system described above.

[0018] The control method for controlling a focused ultrasound system provided by the present invention includes the following steps: Acquire ultrasound image data of the porta hepatis region, which includes the anatomical region where the hepatic artery, portal vein, and bile duct converge; The ultrasound image data is processed to identify the confluence characteristics of the hepatic artery, portal vein, and bile duct in the porta hepatis region, dynamically generate target coordinates, and update the target coordinates in real time based on the displacement data of the porta hepatis region caused by respiratory movements. Based on the real-time updated target coordinates, control commands are generated. These control commands are used to control the robot positioning module to dynamically move the focused ultrasound transducer so that the focal area of ​​the focused ultrasound transducer coincides with the hepatic hilum region at various times during the respiratory cycle. A first control command is generated, which is used to control the focused ultrasound transducer to output low-intensity focused ultrasound according to a first preset parameter.

[0019] The beneficial effects of this invention are as follows: This invention provides a focused ultrasound stimulation system and control method for regulating liver metabolism. The system includes a focused ultrasound transducer, a robot positioning module, an image navigation module, and a control module. The image navigation module acquires ultrasound images of the target region, identifies feature points in the hepatic hilum region, and generates target coordinates. The robot positioning module carries and moves the focused ultrasound transducer. The control module controls the robot positioning module to dynamically move the focused ultrasound transducer according to the real-time updated target coordinates, ensuring its focal zone coincides with the target region, and controls the focused ultrasound transducer to output low-intensity focused ultrasound. This system also provides the application of low-intensity focused ultrasound in the fabrication of a device for treating non-alcoholic fatty liver disease. This system achieves non-invasive physical regulation of liver metabolism, effectively improving lipid deposition and inflammatory states, and has the advantages of automation, precision, and repeatability.

[0020] This invention provides a non-invasive, parameter-controllable, and non-invasive focused ultrasound stimulation system. By targeting the hepatic hilum region, it achieves physical regulation and quantitative observation of hepatic lipid metabolism levels and the expression of inflammation-related factors, providing a standardized and reproducible novel technical platform for research on hepatic metabolic mechanisms and metabolic phenotype regulation. Compared with existing technologies, the focused ultrasound stimulation system and control method for regulating hepatic metabolism provided by this invention have the following beneficial effects: 1. This invention integrates an image navigation module and a robot positioning module to achieve automatic identification and precise spatial positioning of the hepatic hilum region. It can accurately align the focal area of ​​the focused ultrasound transducer with the hepatic hilum region, reduce the positional deviation caused by traditional manual positioning, and improve the positioning accuracy and operational stability of ultrasound energy delivery.

[0021] 2. This invention uses low-intensity focused ultrasound to act on the hepatic hilum region without the need for tissue cutting or invasive operations. It directly regulates the local microenvironment and physiological metabolic state of the liver through physical stimulation, avoiding interference from exogenous substances. It has the advantages of being non-invasive, highly safe, and minimally invasive.

[0022] 3. By setting specific ultrasound parameters, including a center frequency of 0.5 MHz - 2.0 MHz, a peak negative pressure of 0.5 MPa - 3.0 MPa, and a duty cycle of 0.01% - 0.5%, this invention can effectively regulate the level of liver lipid metabolism and the expression level of inflammation-related factors, thereby achieving quantitative regulation and stable control of serum transaminase, lipid-related indicators, liver lipid deposition status, and the expression level of inflammatory factors.

[0023] 4. This invention enables precise setting and timing control of ultrasound parameters through a control module, giving the system good parameter adjustability and operational repeatability. It can optimize and regulate parameters according to the individual characteristics of different experimental subjects, providing a stable and reliable technical foundation for individualized and standardized metabolic regulation research.

[0024] 5. This invention integrates a constant temperature water bath module with the system, ensuring the stability and temperature consistency of the ultrasonic propagation medium, reducing the impact of environmental factors on ultrasonic propagation efficiency, and further improving energy transfer efficiency and system reliability.

[0025] 6. The system architecture of this invention provides a complete hardware platform for the research on automated and standardized regulation of liver metabolism. It can be widely applied to basic research scenarios related to metabolism and has good reproducibility and prospects for widespread application.

[0026] The above and other objects, advantages, and features of the present invention will be more fully set forth and demonstrated through the following detailed description of specific embodiments in conjunction with the accompanying drawings. Those skilled in the art, upon referring to the following detailed description and the accompanying drawings, will be able to better understand and realize the above advantages of the present invention. Other objects, features, and advantages of the present invention will become clearer after being described in detail in the detailed description section in conjunction with the accompanying drawings. Attached Figure Description

[0027] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following drawings are provided for illustration.

[0028] Figure 1 A schematic diagram of a focused ultrasound stimulation system used to regulate liver metabolism; Figure 2 This is a block diagram illustrating the principle of a focused ultrasound stimulation system used to regulate liver metabolism. Figure 3 This is a schematic diagram illustrating the localization of focused ultrasound stimulation of the hepatic hilum region in this embodiment; Figure 4 An overall diagram of the focused ultrasound system; Figure 5 The result of building the NAFLD model is shown in the figure; Figure 6This is a diagram showing the histological changes in the liver after FUS stimulation. Figure 7 The graph shows the results of serum biochemical marker detection after FUS stimulation; Figure 8 The image shows the results of liver TG content detection after FUS stimulation; Figure 9 This is a graph showing the changes in liver inflammatory factors after FUS stimulation.

[0029] In the picture, 1 - Focused ultrasound transducer; 2 - Image navigation module (Ultrasound probe); 3 - Anesthesia machine; 4 - Constant temperature water bath module; 5 - Schematic diagram of the porta hepatis; 6 - Vibration isolation platform; 7 - Robot positioning module; 8 - Signal generator; 9 - Power Amplifier. Detailed Implementation

[0030] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0031] Example 1

[0032] like Figure 1 As shown, Figure 1 This is a schematic diagram of a focused ultrasound stimulation system for regulating liver metabolism. The focused ultrasound stimulation system for regulating liver metabolism provided in this embodiment includes: A focused ultrasound transducer for generating and emitting focused ultrasound, including low-intensity focused ultrasound and high-intensity focused ultrasound; A robot positioning module is used to carry and move the focused ultrasound transducer. The robot positioning module includes a multi-degree-of-freedom robotic arm, and the focused ultrasound transducer is fixedly installed at the end of the multi-degree-of-freedom robotic arm. An image navigation module is used to acquire ultrasound images of the hepatic hilum region in real time, and to identify feature points of the hepatic hilum region based on the ultrasound images to generate target coordinates; wherein, the hepatic hilum region includes the anatomical area where the hepatic artery, portal vein and bile duct converge; the image navigation module includes an ultrasound probe and an image processing unit, the image processing unit being used to identify the confluence features of the hepatic artery, portal vein and bile duct in the hepatic hilum region and to calculate the target coordinates; A constant temperature water bath module is used to contain degassed water and maintain a preset water temperature, wherein the focused ultrasonic transducer and the target area are immersed in the degassed water; The control module is connected to the focused ultrasound transducer, the robot positioning module, the image navigation module, and the constant temperature water bath module, respectively. The control module is configured as follows: The image navigation module is controlled to acquire ultrasound images of the porta hepatis region in real time, identify feature points in the porta hepatis region, dynamically generate target coordinates, and update the target coordinates in real time according to the displacement of the porta hepatis region caused by respiratory movements. Based on the target coordinates updated in real time, the robot positioning module is controlled to dynamically move the focused ultrasound transducer so that the focal area of ​​the focused ultrasound transducer coincides with the hepatic hilum region at various times during the respiratory cycle. The focused ultrasound transducer is controlled to output low-intensity focused ultrasound according to a first preset parameter to provide non-invasive stimulation to the porta hepatis region; and The focused ultrasound transducer is controlled to output high-intensity focused ultrasound according to the second preset parameters in order to ablate the tissue in the porta hepatis region.

[0033] In this embodiment, the focused ultrasound transducer is controlled to output low-intensity focused ultrasound according to a first preset parameter to stimulate the porta hepatis region, thereby achieving liver metabolic regulation. The first preset parameter is configured to reduce liver triglyceride levels, decrease serum transaminase levels, increase serum high-density lipoprotein levels, and decrease the expression levels of liver inflammatory factors TNF-α and IL-1β. Furthermore, when lesions are detected in the porta hepatis region, the focused ultrasound transducer is controlled to output high-intensity focused ultrasound according to a second preset parameter to ablate the tissue. The second preset parameter is configured to induce coagulative necrosis in the tissue.

[0034] The image navigation module described in this embodiment includes an ultrasound probe and an image processing unit; The ultrasound probe is used to acquire ultrasound images of the hepatic hilum region; The image processing unit is used to process the ultrasound image and identify feature points in the hepatic hilum region to generate the target coordinates.

[0035] In this embodiment, the image processing unit includes a coordinate calibration subunit, which is used to establish the spatial transformation relationship between the image coordinate system of the ultrasonic probe and the mechanical coordinate system of the robot positioning module.

[0036] The robot positioning module in this embodiment includes a multi-degree-of-freedom robotic arm and a servo driver. The focused ultrasound transducer is fixedly installed at the end of the multi-degree-of-freedom robotic arm, and the servo driver drives the multi-degree-of-freedom robotic arm to move according to the instructions of the control module.

[0037] In this embodiment, the center frequency of the focused ultrasound transducer is 0.5 MHz-2.0 MHz, the peak negative pressure is 0.5 MPa-3.0 MPa, and the low-intensity focused ultrasound is a pulse wave with a duty cycle of 0.01%-0.5%.

[0038] The control module in this embodiment further includes a parameter setting unit and a timing control unit. The parameter setting unit is used to set the output parameters of the focused ultrasound transducer, and the timing control unit is used to control the focused ultrasound transducer to output ultrasound according to a preset treatment cycle. The treatment cycle includes once a day, with each irradiation lasting 1 to 10 minutes, for 1 to 8 weeks. In this embodiment, the focused ultrasound transducer can be driven by adjusting the control module to generate focused ultrasound signals of different intensities.

[0039] This embodiment also includes a constant temperature water bath module, which is used to contain degassed water and maintain it within a preset water temperature range. The focused ultrasonic transducer and the target area are immersed in the degassed water. In this embodiment, the preset water temperature range is set to between 30°C and 40°C. In this embodiment, the focused ultrasound transducer is a phased array transducer, and the control module is further configured to achieve electronic focusing on the hepatic hilum region by adjusting the excitation signal delay of each element of the phased array transducer.

[0040] like Figure 2 As shown, Figure 2 This is a block diagram illustrating the principle of a focused ultrasound stimulation system used to regulate liver metabolism. The diagram clearly shows the signal flow, energy flow, feedback, and coupling relationships between the various modules, as detailed below: The control module, signal generator, and power amplifier are connected in series to form the main signal path. The control module sends control signals to the signal generator to set the ultrasound output parameters (including center frequency, pulse width, repetition frequency, and duty cycle). The signal generator generates a corresponding low-voltage electrical signal according to the instructions and sends it to the power amplifier. The power amplifier amplifies the electrical signal to a voltage and power level sufficient to drive the focused ultrasound transducer, outputting driving energy to the transducer.

[0041] The control module and the robot positioning module achieve bidirectional communication: the control module sends position commands to the robot positioning module, and the robot positioning module returns the actual position status. The robot positioning module drives the multi-degree-of-freedom robotic arm to move according to the commands. A focused ultrasound transducer is fixedly installed at the end of the robotic arm, thereby driving the transducer to move in three-dimensional space, ensuring that the transducer's focal area is precisely aligned with the hepatic hilum region.

[0042] The image navigation module (ultrasound probe) scans the hepatic hilum region in real time, acquiring ultrasound images. The image processing unit identifies the confluence features of the hepatic artery, portal vein, and bile ducts, dynamically generating target coordinates. These target coordinates are transmitted to the control module as a feedback signal in the form of real-time image / target coordinates. The control module updates the robot's positioning module's trajectory accordingly, forming a closed-loop control system to compensate for target displacement caused by respiratory movements, etc.

[0043] The focused ultrasound transducer receives driving energy from the power amplifier and mechanical motion from the robot positioning module to generate focused ultrasound energy, which is then applied to the target area—the porta hepatis. The porta hepatis is the anatomical region where the hepatic artery, portal vein, and bile duct converge, and it is the key site of action for this invention to achieve liver metabolic regulation.

[0044] The constant-temperature water bath module, anesthesia machine, and vibration isolation platform form a physical coupling or environmental support relationship with the core module: the constant-temperature water bath module contains degassed water and maintains a preset water temperature (30℃~40℃) through a constant-temperature heater. The focused ultrasound transducer and the porta hepatis are immersed in the degassed water, achieving efficient coupling and transmission of ultrasound energy while avoiding bubble interference and skin burns; the anesthesia machine provides anesthetic gas to experimental animals or patients, ensuring that they remain stationary during treatment and reducing motion artifacts and accidental displacement; the vibration isolation platform provides stable mechanical support for the robot positioning module and experimental subjects, effectively attenuating external environmental vibrations and ensuring positioning accuracy and the stability of ultrasound action.

[0045] The control method based on the above-described focused ultrasound stimulation system and control method for regulating liver metabolism provided in this embodiment includes the following steps: The control method based on the above-described focused ultrasound stimulation system for regulating liver metabolism provided in this embodiment includes the following steps: Step S1: Acquire ultrasound images of the hepatic hilum region in real time. The ultrasound probe in the control image navigation module acquires ultrasound images of the hepatic hilum region in real time, wherein the hepatic hilum region includes the anatomical area where the hepatic artery, portal vein, and bile duct converge.

[0046] Step S2: Identify features of the hepatic hilum region and dynamically generate target coordinates. The image processing unit in the control image navigation module processes the ultrasound image, identifies the confluence characteristics of the hepatic artery, portal vein, and bile duct in the porta hepatis region, dynamically generates target coordinates, and updates the target coordinates in real time based on the displacement of the porta hepatis region caused by respiratory movements.

[0047] Step S3: Dynamically move the focused ultrasound transducer to keep the focal zone aligned with the porta hepatis region. Based on the target coordinates updated in real time, the robot positioning module is controlled to dynamically move the focused ultrasound transducer so that the focal area of ​​the focused ultrasound transducer coincides with the hepatic hilum region at various times during the respiratory cycle.

[0048] Step S4: Output low-intensity focused ultrasound for liver metabolic regulation The focused ultrasound transducer is controlled to output low-intensity focused ultrasound according to a first preset parameter to stimulate the hepatic hilum region, thereby achieving liver metabolic regulation. The first preset parameter includes: a center frequency of 0.5 MHz to 2.0 MHz, a peak negative pressure of 0.5 MPa to 3.0 MPa, a pulse wave, a duty cycle of 0.01% to 0.5%, a single stimulation duration of 1 minute to 10 minutes, and a treatment cycle of once daily for 1 to 8 weeks.

[0049] Step S5: When lesion tissue is detected, high-intensity focused ultrasound is output for ablation. During stimulation, ultrasound images of the hepatic hilum region are monitored in real time. When lesions are detected in the hepatic hilum region, the focused ultrasound transducer is controlled to output high-intensity focused ultrasound according to a second preset parameter to ablate the lesion. The second preset parameter includes: a center frequency of 0.5 MHz to 2.0 MHz, a peak negative pressure of 3.0 MPa to 10.0 MPa, and a continuous wave or a pulse wave with a duty cycle greater than 50%.

[0050] Example 2

[0051] This embodiment provides a method for using a focused ultrasound stimulation system and control method for regulating liver metabolism. The method is for scientific research purposes, regulating and observing the physiological metabolic state of the liver in mammalian individuals. The method includes the following steps: (1) Construction and grouping of experimental animal models In this embodiment, SPF-grade male C57BL / 6J mice were used as experimental subjects. The experimental animals were housed in a constant temperature and humidity environment, with the ambient temperature maintained at 22±2℃, the relative humidity at 50%~60%, and the light cycle at 12h light / 12h dark. All mice had free access to food and water.

[0052] The experimental mice were randomly divided into a normal control group (ND) and a high-fat diet group (HFD). The normal control group was fed a standard diet, while the high-fat diet group was fed a high-fat diet with 60% fat as its energy source. The mice were fed this diet for 22 weeks to establish an animal model with metabolic features such as obesity and hepatic lipid deposition.

[0053] After the model was built, the experimental mice were randomly divided into three groups: Normal control group (Normal), fed standard feed, N=6; Control group (Sham), 60% high-fat diet, N=6; The ultrasonically treated group (Treated) was fed a 60% high-fat diet with N=6.

[0054] In the ultrasound treatment group, focused ultrasound intervention was applied using this system; the control group followed the same procedure as the ultrasound treatment group, except that the probe did not output energy. All mice maintained their original feeding conditions during the experiment.

[0055] (2) This system was used to apply low-intensity focused ultrasound to the hepatic hilum region of experimental animals. The low-intensity focused ultrasound control parameters used in this system are: The center frequency is 1.035MHz, the peak negative pressure is 1.87MPa, the pulse wave form is used, the duration of a single pulse is 0.15ms, the pulse period is 200ms, the duty cycle is 0.075%, the single continuous irradiation is 3 minutes, once a day, and the treatment is carried out continuously for 5 weeks.

[0056] The hepatic hilum region is the confluence of the hepatic artery, portal vein, and bile duct. This region is rich in blood vessels, nerves, and mechanically sensitive structures, which can produce a physiological response to focused ultrasound stimulation.

[0057] The single-use process is as follows: 1. Before the initial treatment, the mice underwent hair removal on their abdomens, with subsequent treatments performed based on hair growth. Degassed water was prepared using a vacuum degassing system and heated to a constant temperature of 35°C before use.

[0058] 2. Mice were anesthetized using an isoflurane gas anesthesia system. Rapid induction was performed in an induction box at a concentration of 3-4% and a flow rate of 0.5 L / min. Once the mice were in a stable anesthetized state, they were transferred to a custom-made fixation plate, and anesthesia was maintained through the nasal cavity at a concentration of 1.5-2% and a flow rate of 0.3 L / min. The fixation plate was then immersed in a water bath, and its position was adjusted so that the mouse's abdomen was completely submerged.

[0059] 3. Through the robot positioning module and image navigation module of this system, the B-ultrasound probe is driven to scan the hepatic hilum region, acquire two-dimensional images and mark the target coordinates; the system automatically plans the motion path according to the spatial relationship between the probe and the transducer and the focal length parameters, completes the positioning, and makes the focal area of ​​the transducer coincide with the hepatic hilum region.

[0060] 4. Start the focused ultrasound output and execute the irradiation procedure according to the set parameters. After treatment, stop the output, remove the mouse, dry it, and place it on a 37°C constant temperature pad to recover. After it regains consciousness, return it to its cage.

[0061] 5. Mice in the control group underwent all procedures except for ultrasound output, including hair removal, anesthesia, fixation, positioning, and transducer movement.

[0062] (3) Observation and analysis of liver metabolism and tissue physiological state After the experiment, samples were collected and indicators were tested from all groups of mice to observe changes in liver metabolism and tissue physiological state. The specific steps are as follows: 1. Sample Collection: Mice were fasted for 12 hours but allowed free access to water. Blood samples were collected via the orbital rim under anesthesia. After standing at room temperature for 2 hours, the samples were centrifuged at 3000 rpm for 15 minutes, and the supernatant serum was collected and stored at -80°C. Liver tissue was harvested, washed with pre-cooled PBS, and dried. After weighing, a portion of the right lobe of the liver was fixed in 4% paraformaldehyde. The remaining tissue was aliquoted, rapidly frozen in liquid nitrogen, and then transferred to -80°C for storage.

[0063] 2. Histomorphological observation: The fixed liver tissue was paraffin-embedded, serially sectioned, and then dewaxed, stained with hematoxylin and eosin (HE), dehydrated, and mounted. The tissue was observed and images were acquired under a microscope. Frozen sections were stained with Oil Red O to observe the lipid distribution in the tissue.

[0064] 3. Biochemical index detection: The triglyceride (TG) content in liver tissue was detected using a kit; the AST, ALT, TG, TC, HDLC, and LDLC content in serum was detected using a fully automated biochemical analyzer.

[0065] 4. Cytokine level detection: The serum levels of IL1β, IL6, and TNFα were detected using the ELISA method.

[0066] Through the above steps, the regulation and observation of liver metabolic pathways, expression of inflammation-related factors, and tissue lipid deposition status can be achieved, verifying the system's ability to regulate the physiological metabolic state of the liver.

[0067] The system provided in this embodiment uses low-intensity focused ultrasound to target the hepatic hilum region without the need for tissue cutting or invasive procedures. It is highly non-invasive and has a high overall safety profile. It can achieve stable and repeatable regulation of hepatic lipid metabolism levels and the expression of inflammation-related factors. Metabolic regulation is achieved through pure physical stimulation without the intervention of exogenous drugs, resulting in minimal experimental interference and high reliability of results. The system parameters are adjustable and the process is standardized, making it suitable for various research scenarios on hepatic metabolic regulation and demonstrating good practicality and application prospects.

[0068] like Figure 3 As shown, Figure 3 This is a schematic diagram illustrating the localization of focused ultrasound stimulation of the hepatic hilum region in this embodiment. This embodiment shows a schematic diagram of the location of focused ultrasound stimulation of the hepatic hilum region.

[0069] The experimental subject was fixed to the experimental platform in a stable state. The ultrasound probe was moved using a robotic positioning module to locate the hepatic hilum region and centered it in the image. The distance from the hepatic hilum region to the body surface was measured. Using 3D scanning technology and SOLIDWORKS 2021, a fixture drawing connecting the focused ultrasound transducer and the ultrasound probe was created. This fixture was then 3D printed, fixing the ultrasound probe at a specific distance below the ultrasound transducer. Based on the transducer's focal length and the relative position of the ultrasound probe and the transducer, the transducer was moved to align the focused ultrasound area with the hepatic hilum region, achieving targeted and directional ultrasound action.

[0070] This system offers higher positioning accuracy and more precise ultrasound application. Through the coordinated operation of the image navigation module and the robot positioning module, it can automatically identify the hepatic hilum region and complete spatial positioning, ensuring precise alignment between the ultrasound focusing area and the target area, reducing positioning deviation, and improving the accuracy and consistency of ultrasound energy application.

[0071] Figure 4 This is a schematic diagram of the overall structure of the focused ultrasound control system of the present invention. To achieve precise ultrasound targeting of the hepatic hilum region, this embodiment constructs a focused ultrasound control system, which mainly consists of a signal generator, a power amplifier, a focused ultrasound transducer, and a robot positioning module. The red dotted line in the diagram represents the system positioning module. The signal generator generates an electrical signal of a set frequency and pulse form. Its output signal is amplified by the power amplifier and then drives the focused ultrasound transducer to generate ultrasound waves. The positioning module is used to determine the location of the ultrasound stimulation and ensure that the ultrasound focus can accurately target the hepatic hilum region of the mouse. During the experiment, the mouse is fixed to the experimental platform under anesthesia. The diagnostic ultrasound equipment used in the image navigation module is equipped with a customized high-frequency ultrasound probe, which can provide an examination frequency of 12-25MHz. The robot positioning module includes a multi-degree-of-freedom robotic arm, which can provide six degrees of freedom of motion and a repeatability accuracy of ±0.03 mm, enabling high-precision positioning. The power amplifier can provide stable electrical power output to ensure that the transducer operates stably under the set parameters. The signal generator and the power amplifier constitute the control system. The focused ultrasound transducer is the core component of the system. It can convert electrical energy into mechanical vibration, thereby generating ultrasound waves of a specific frequency and forming a high-energy-density sound field in the focal region.

[0072] The control module adjusts ultrasound output parameters, including center frequency, pulse width, repetition rate, and duty cycle, to meet experimental requirements. The positioning system determines the location of ultrasound stimulation and ensures that the ultrasound focus is accurately applied to the hepatic hilum region of the mouse. During the experiment, the mice are anesthetized and fixed to the experimental platform.

[0073] The diagnostic ultrasound equipment used in the image navigation and positioning module is equipped with a customized high-frequency ultrasound probe, providing an examination frequency of 12-25MHz, thus achieving high-resolution imaging. It can perform high-precision examinations of superficial tissues up to 5 mm in diameter, and also achieve an examination depth of 50 mm, completely covering the tissues and organs of mice and rats. The robot used provides six degrees of freedom of motion, allowing for convenient free movement in three-dimensional space. Each joint can rotate ±360°, and the working range is a spherical space with a radius of 1.35 m, fully meeting experimental requirements. It provides a 10 kg payload, enabling movement of the ultrasound transducer and B-mode ultrasound probe; the repeatability is as high as ±0.03 mm, achieving high-precision positioning. The robot can operate in environments of 0-45℃ and 25%-85% humidity; its movement speed is 0.04 m / s to 4 m / s, facilitating B-mode ultrasound examinations. Using 3D scanning technology and SOLIDWORKS 2021, a tooling drawing for connecting the transducer and the ultrasound probe was created. Then, the tooling shown in the figure was 3D printed. This tooling fixes the ultrasound probe to the bottom of the ultrasound transducer in a certain relative position.

[0074] Figure 5 This diagram illustrates the results of constructing the metabolic model for the experimental subjects. HFD represents the high-fat diet group, and ND represents the normal control group. A: Comparison of body size and liver appearance of the subjects under different feeding conditions (HFD on the left, ND on the right); B: Comparison of body weight changes and liver weight of the subjects; C: Results of HE staining and Oil Red O staining of liver tissue. In the diagram, the symbols *, **, ***, and ns have the following meanings in biomedicine and statistics: ns indicates P > 0.05, * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001, and **** indicates P < 0.0001. The results showed that the body size and liver volume of the high-fat diet group were significantly larger than those of the normal control group. From week 4 onwards, the weight gain rate of the high-fat diet group significantly exceeded that of the normal control group. By week 12, the average weight of the high-fat diet group reached 35.2 ± 1.5 g, while that of the normal control group was only 28.6 ± 0.9 g. During the stable period from week 12 to week 22, the weight of the high-fat diet group continued to increase slowly, eventually reaching 42.5 ± 2.1 g. The liver wet weight of the high-fat diet group was significantly increased compared to the normal control group (P < 0.01). HE staining of liver tissue in the high-fat diet group showed numerous lipid droplet vacuoles, inflammatory infiltration, and necrosis in hepatocytes; Oil Red O staining showed a large distribution of red lipid droplets, indicating significant hepatic steatosis. These results confirmed the successful establishment of the model.

[0075] Figure 6This is a schematic diagram of the morphological changes in liver tissue after ultrasound treatment. HE staining was used to observe changes in liver tissue structure, and OilRed O staining was used to assess lipid deposition in liver tissue. Normal represents the normal control group, Sham represents the control treatment group, and Treated represents the ultrasound treatment group.

[0076] The results showed that in the normal control group, hepatocytes were neatly arranged, the hepatic cords were clearly defined, and the cell morphology was intact, with no obvious lipid droplets or inflammatory cell infiltration. In the control group, numerous lipid droplets and vacuoles were observed in the hepatocytes, some hepatocytes showed obvious fatty degeneration, the hepatic cord structure was disordered, and there was a certain degree of inflammatory cell infiltration. Compared with the control group, after focused ultrasound treatment, the number of lipid droplets in the liver tissue of the ultrasound-treated group was significantly reduced, the vacuolar structure was significantly decreased, the hepatocyte morphology was more intact, the liver tissue structure was somewhat restored, and the degree of inflammatory cell infiltration was reduced, but overall it had not completely recovered to the normal level. The results indicate that FUS treatment can improve high-fat diet-induced hepatic steatosis and tissue structural damage to a certain extent.

[0077] like Figure 7 As shown, Figure 7 This diagram illustrates the changes in serum biochemical parameters after ultrasound treatment, including liver function markers (ALT, AST) and lipid metabolism markers (HDL, TC, TG, LDL). Normal represents the normal control group, Sham represents the control group, and Treated represents the ultrasound treatment group. In the diagram, A: changes in serum ALT levels; B: changes in serum AST levels; C: changes in serum HDL levels; D: changes in serum TC levels; E: changes in serum TG levels; F: changes in serum LDL levels. (ns P > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001).

[0078] The results showed that serum ALT and AST levels in the high-fat diet group were higher than those in the normal control group (P<0.05), indicating liver function damage induced by the high-fat diet. After ultrasound treatment with this system, ALT and AST levels in the ultrasound-treated group were significantly reduced (P<0.05), suggesting that ultrasound stimulation has a certain protective effect on liver function. Serum HDL levels in the normal control group were higher than those in the high-fat diet group (P<0.05), while HDL levels in the ultrasound-treated group were significantly increased after ultrasound treatment (P<0.0001). Serum TC, TG, and LDL levels in the high-fat diet group were all higher than those in the normal control group (P<0.05), while TC, TG, and LDL levels in the ultrasound-treated group were significantly reduced after ultrasound treatment (P<0.05), suggesting the regulatory effect of ultrasound on lipid metabolism. These results demonstrate the regulatory effect of the system of this invention on liver function damage and lipid metabolism induced by a high-fat diet.

[0079] Figure 8 This is a schematic diagram showing the changes in TG content in liver tissue after ultrasound treatment, used to quantitatively assess lipid deposition in the liver. Normal represents the normal control group, Sham represents the control group, and Treated represents the ultrasound treatment group. (ns P > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001).

[0080] The results showed that after the focused ultrasound of the present invention, the TG content in the liver tissue of the ultrasound-treated group was significantly lower than that of the control group (P<0.05), indicating that the system can effectively regulate the lipid content level in the liver tissue.

[0081] Figure 9 This diagram illustrates the changes in the expression levels of liver inflammation-related factors after ultrasound treatment, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). These inflammatory factors exacerbate hepatocyte damage and intensify the liver's inflammatory response. Normal represents the normal control group, Sham represents the control group, and Treated represents the ultrasound treatment group. In the diagram, A represents IL-1β expression level; B represents TNF-α expression level; and C represents IL-6 expression level. (ns P > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001).

[0082] The results showed that the expression levels of TNF-α and IL-1β in the liver tissue of the high-fat diet group were increased; after ultrasound treatment by this system, the expression levels of TNF-α and IL-1β in the ultrasound treatment group were significantly reduced (P<0.05); the expression level of IL-6 showed a decreasing trend; indicating that the system of the present invention can regulate the expression levels of liver inflammation-related factors.

[0083] The system provided in this embodiment limits the target coordinates to the porta hepatis region (the confluence of the hepatic artery, portal vein, and bile ducts). Unlike existing technologies that rely on nerve transection or invasive procedures, this application directly stimulates the porta hepatis region physically, regulating liver metabolism without neural mediation, thus overcoming technological bias. Secondly, this region selection brings unexpected technical effects: Example 2 demonstrates that precise stimulation of the porta hepatis region can simultaneously reduce liver triglyceride levels, decrease serum transaminase levels, increase high-density lipoprotein levels, and inhibit the expression of inflammatory factors TNF-α and IL-1β. This multifunctional synergistic effect cannot be derived from stimulating any arbitrary location on the liver. Finally, the porta hepatis region has distinct anatomical features in ultrasound imaging, enabling the image navigation module to automatically and stably generate target coordinates, thereby achieving precise robot positioning and overcoming the shortcomings of poor positioning accuracy and reliance on experience in existing technologies. Therefore, this technical feature gives this application outstanding substantive characteristics and significant progress.

[0084] The embodiments described above are merely preferred embodiments for fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A focused ultrasound stimulation system for regulating liver metabolism, characterized in that, It includes a focused ultrasound transducer, a robot positioning module, an image navigation module, and a control module; The focused ultrasound transducer is used to generate and emit focused ultrasound, including low-intensity focused ultrasound and high-intensity focused ultrasound. The robot positioning module is used to carry and move the focused ultrasound transducer. The robot positioning module includes a multi-degree-of-freedom robotic arm, and the focused ultrasound transducer is fixedly installed at the end of the multi-degree-of-freedom robotic arm. The image navigation module is used to acquire ultrasound images of the target area and identify feature points in the hepatic hilum region based on the ultrasound images to generate target point coordinates. The porta hepatis region includes the anatomical area where the hepatic artery, portal vein, and bile duct converge; the image navigation module includes an ultrasound probe and an image processing unit, the image processing unit being used to identify the convergence features of the hepatic artery, portal vein, and bile duct in the porta hepatis region and to calculate the target coordinates; The control module is connected to the focused ultrasound transducer, the robot positioning module, and the image navigation module, respectively, and the control module is configured as follows: The image navigation module is controlled to acquire ultrasound images of the porta hepatis region in real time, identify feature points in the porta hepatis region, dynamically generate target coordinates, and update the target coordinates in real time according to the displacement of the porta hepatis region caused by respiratory movements. Based on the target coordinates updated in real time, the robot positioning module is controlled to dynamically move the focused ultrasound transducer so that the focal area of ​​the focused ultrasound transducer coincides with the hepatic hilum region at various times during the respiratory cycle. The focused ultrasound transducer is controlled to output low-intensity focused ultrasound according to a first preset parameter to provide non-invasive stimulation to the porta hepatis region; and The focused ultrasound transducer is controlled to output high-intensity focused ultrasound according to the second preset parameters in order to ablate the tissue in the porta hepatis region.

2. The focused ultrasound stimulation system for regulating liver metabolism as described in claim 1, characterized in that, The low-intensity focused ultrasound output by the first preset parameter can cause at least one of the following changes in the target liver tissue: It reduces liver triglyceride levels, lowers serum transaminase levels, increases serum high-density lipoprotein levels, lowers serum low-density lipoprotein levels, lowers serum total cholesterol levels, lowers serum triglyceride levels, lowers fasting blood glucose levels, lowers glycated hemoglobin levels, and reduces the expression levels of liver inflammatory factors TNF-α and IL-1β.

3. The focused ultrasound stimulation system for regulating liver metabolism as described in claim 1, characterized in that, The image navigation module is used to plan target points and establish a coordinate system before treatment, to monitor the focal zone position and target point offset in real time during treatment, and to evaluate target area coverage after treatment.

4. The focused ultrasound stimulation system for regulating liver metabolism as described in claim 1, characterized in that, The image processing unit includes a coordinate calibration subunit, which is used to establish the spatial transformation relationship between the image coordinate system of the ultrasonic probe and the mechanical coordinate system of the robot positioning module.

5. The focused ultrasound stimulation system for regulating liver metabolism as described in claim 1, characterized in that, The robot positioning module includes a servo driver, which drives the multi-degree-of-freedom robotic arm to move according to the instructions of the control module.

6. The focused ultrasound stimulation system for regulating liver metabolism as described in claim 1, characterized in that, When the focused ultrasound transducer emits low-intensity ultrasound, its center frequency is 0.5 MHz-2.0 MHz, the peak negative pressure is 0.5 MPa-3.0 MPa, the pulse wave has a duty cycle of 0.01%-0.5%. When the focused ultrasound transducer emits high-intensity ultrasound, its center frequency is 0.5 MHz-2.0 MHz, the peak negative pressure is 3.0 MPa-10.0 MPa, and it emits continuous waves or pulse waves with a duty cycle greater than 50%.

7. The focused ultrasound stimulation system for regulating liver metabolism as described in claim 1, characterized in that, The focused ultrasound transducer is a phased array transducer, and the control module is further configured to achieve electronic focusing on the hepatic hilum region by adjusting the excitation signal delay of each element of the phased array transducer.

8. The focused ultrasound stimulation system for regulating liver metabolism as described in claim 1, characterized in that, It also includes a constant temperature water bath module connected to the control module, used to contain degassed water and maintain a preset water temperature, wherein the focused ultrasonic transducer and the target area are immersed in the degassed water.

9. The application of low-intensity focused ultrasound in the fabrication of a device for treating non-alcoholic fatty liver disease, characterized in that, The device is the system according to any one of claims 1-8.

10. A control method for controlling a focused ultrasound system, characterized in that, Includes the following steps: Acquire ultrasound image data of the porta hepatis region, which includes the anatomical region where the hepatic artery, portal vein, and bile duct converge; The ultrasound image data is processed to identify the confluence characteristics of the hepatic artery, portal vein, and bile duct in the porta hepatis region, dynamically generate target coordinates, and update the target coordinates in real time based on the displacement data of the porta hepatis region caused by respiratory movements. Based on the real-time updated target coordinates, control commands are generated. These control commands are used to control the robot positioning module to dynamically move the focused ultrasound transducer so that the focal area of ​​the focused ultrasound transducer coincides with the hepatic hilum region at various times during the respiratory cycle. Generate a first control command, which is used to control the focused ultrasound transducer to output low-intensity focused ultrasound according to a first preset parameter; In addition, a second control command is generated, which is used to control the focused ultrasound transducer to output high-intensity focused ultrasound according to a second preset parameter.

Images