An intracranial precise drug delivery method and system integrating craniotomy positioning and injection

Abstract

The present application relates to the technical field of intracranial administration, in particular to an integrated intracranial precise administration method and system for craniotomy positioning and injection, laser cutting and injection parameters are determined according to the type of target animal, then a skull overhead image is collected to obtain the mechanical coordinates of the target point, and then the laser craniotomy unit is controlled to perform layered cutting to expose the dura mater, finally the target point coordinates are calibrated and the injection execution unit is driven to complete precise puncture, administration and needle withdrawal, avoiding the brain shift risk caused by the disconnection of the craniotomy and injection process, significantly improving the repeatability and precision of target positioning and administration, reducing the dependence on the experience of operators, and being especially suitable for the intracranial precise administration experimental needs of small animals such as mice.

Description

Technical Field

[0001] This invention relates to the field of intracranial drug delivery technology, specifically to a method and system for precise intracranial drug delivery that integrates craniotomy, localization, and injection. Background Technology

[0002] Precise intracranial drug delivery is a core experimental technique for constructing animal models, conducting brain function studies, and verifying drug efficacy. Currently, conventional intracranial drug delivery experiments in mice require first manually opening the skull to expose the target area beneath the skull, and then using a stereotaxic instrument to align the injection needle with the target and perform the drug delivery.

[0003] However, manual mechanical craniotomy is difficult to control in terms of the extremely thin skull of mice (0.2-0.8 mm), heavily reliant on operator experience, and prone to causing damage to the dura mater and cortical brain tissue. Furthermore, the craniotomy procedure is disconnected from the targeted injection process, leading to brain displacement after craniotomy, resulting in insufficient accuracy in locating small nuclei and poor experimental repeatability. Insufficient precision in controlling injection depth and administration rate during injection can easily lead to drug leakage along the needle tract, affecting the accuracy of experimental results. Existing high-precision drug delivery systems mostly rely on preoperative CT / MRI image import for target planning, which has high equipment requirements and complex operating procedures, making it difficult to adapt to the standardized stereotactic brain localization experiments in conventional laboratories and failing to meet drug delivery needs. Summary of the Invention

[0004] The purpose of this invention is to provide a method and system for precise intracranial drug delivery that integrates craniotomy positioning and injection, thereby solving the technical problems of low precision and complex procedures in current craniotomy positioning and injection procedures.

[0005] The solution of the present invention to the above-mentioned technical problems is as follows: A method for precise intracranial drug delivery integrating craniotomy and localization injection includes the following steps: Based on the target animal type, determine the laser cutting parameters and injection parameters; The target animal is fixed in place, and a top-view image of the target animal's skull is acquired through the image acquisition unit to obtain the mechanical coordinates of the target point; The laser craniotomy unit, controlled by laser cutting parameters, performs layered cutting of the target animal's skull until the dura mater is exposed. The mechanical coordinates of the target point are calibrated, and the injection execution unit is driven to position the injection needle to the target point. The injection execution unit controls the injection needle to puncture, administer medication, and withdraw the needle towards the target site based on injection parameters.

[0006] Further specifying, the determination of laser cutting parameters and injection parameters based on the target animal type includes the following steps: Match the corresponding stereotaxic atlas data model to the target animal species and age strain; In the brain stereotactic mapping data model, the cutting region and cutting shape are determined, and the corresponding cutting power, cutting speed, number of cutting layers, cutting thickness and pulse width are matched. Select target points in the brain stereotaxic mapping data model and obtain the model coordinates of the target points; Set the injection angle, puncture speed, injection dose, injection speed, and needle withdrawal speed.

[0007] Further specifying, the fixed target animal, obtaining the mechanical coordinates of the target point by acquiring a top-view image of the target animal's skull through an image acquisition unit includes the following steps: Fix the target animal on the workbench and adjust the angle of the target animal's head so that the height difference between its anterior and posterior fontanelles is ≤0.01mm; The image acquisition unit acquires a top view of the target animal's skull, and the image boundary is enhanced by a filter to obtain a top view image of the target animal's skull. Identify the anterior and posterior fontanelle markers, as well as their two-dimensional image coordinates, based on a top-view image of the target animal's skull; The line connecting the anterior and posterior fontanelle markers is used as the initial longitudinal axis. The yaw error of the initial longitudinal axis is corrected by the sagittal suture of the skull to obtain a positioning longitudinal axis that coincides with the sagittal suture of the skull. On the cranial sutures on both sides of the positioning longitudinal axis, select suture markers with a perpendicular distance X from the positioning longitudinal axis, and obtain the two-dimensional image coordinates of the two suture markers respectively; Based on hand-eye calibration, the two-dimensional image coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone seam markers are converted into corresponding two-dimensional mechanical coordinates; Using a vertical rangefinder, the vertical distances of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seam markers were obtained at the same height, and the three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seam markers were obtained respectively. Based on the three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone suture markers, and their three-dimensional model coordinates in the brain stereotaxic mapping data model, the affine transformation matrix mapping the model coordinates to the mechanical coordinates is obtained. Based on the affine transformation matrix, the model coordinates of the target point are converted into the mechanical coordinates of the target point.

[0008] Further specifying, obtaining the affine transformation matrix mapping the model coordinates to the machine coordinates includes the following steps: The affine transformation matrix mapping the model coordinates to the machine coordinates is obtained through the ICP iterative nearest point algorithm. ; Calculate the affine transformation matrix error :

[0009] in, The number of markers, For the first Model coordinates of each marker point For the first The mechanical coordinates of each marker point; Determine the affine transformation matrix error Check if the mapping error is satisfied; if yes, end the process; otherwise, re-obtain the affine transformation matrix. Continue until the mapping error is satisfied.

[0010] Further specifying, the laser craniotomy unit controlling laser cutting parameters to perform layered cutting of the target animal's skull until the dura mater is exposed includes the following steps: Based on the mapping relationship, the cutting path of the laser craniotomy unit is determined according to the cutting shape in the brain stereotactic mapping data model. The laser craniotomy unit operates at low power along the cutting path. By optimizing the cutting path, the deviation between the current cutting area and the target cutting area meets the cutting error. The laser craniotomy unit is activated, and the target animal's skull is cut layer by layer according to the determined laser cutting parameters until the dura mater is exposed. Turn off the laser craniotomy unit.

[0011] Further specifying, the step of performing layered cutting of the target animal skull according to the determined laser cutting parameters includes the following steps: The top view of the skull cutting is acquired in real time by the image acquisition unit, and the laser cutting boundary is obtained by using the Hessian matrix and the Frangi filter on the top view of the skull cutting. The top view of the skull cut is used to obtain the laser cutting boundary through a Hessian matrix and a Frangi filter. The cutting path is adjusted in real time based on the deviation between the laser cutting boundary and the target cutting path; After each layer of the skull is cut, the remaining skull thickness is obtained using a vertical rangefinder; The cutting power and speed are optimized based on the remaining skull thickness until the last layer of skull is cut.

[0012] Further specifying, the optimization of cutting power and cutting speed based on the remaining skull thickness includes the following steps: Calculate the cutting error of the current layer :

[0013] in, This represents the theoretical remaining skull thickness after the current k-th layer is cut. This represents the actual remaining skull thickness after the current k-th layer is cut. when At the same time, increase the cutting power of the next layer and reduce the cutting speed; when At this time, reduce the cutting power of the next layer and increase the cutting speed.

[0014] Further defining the step of calibrating the mechanical coordinates of the target point and driving the injection execution unit to position the injection needle to the target point includes the following steps: The three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seams are re-acquired using the image acquisition unit and the vertical rangefinder, and it is determined whether the offset error is exceeded. If so, the mechanical coordinates of the target point are re-determined. Based on the determined mechanical coordinates of the target point, the injection execution unit is controlled to move the injection needle directly above the target point.

[0015] Further defining the procedure, the injection execution unit controls the injection needle to puncture, administer medication, and withdraw the needle towards the target point based on injection parameters, including the following steps: The injection needle is controlled to penetrate the target point at a set injection angle and puncture speed. The injection is controlled to deliver the drug to the target site according to the set injection dose and injection speed. The injection execution unit controls the injection needle to complete the withdrawal according to the set withdrawal speed.

[0016] A craniotomy-guided, localized, and precisely administered intracranial drug delivery system, used to implement the aforementioned craniotomy-guided, localized, and precisely administered intracranial drug delivery method, comprising: The image acquisition unit is used to acquire a top-view image of the skull of a fixed target animal; The host computer is used to obtain the mechanical coordinates of the target point based on the acquired top view image of the skull, and is used to calibrate the mechanical coordinates of the target point. The laser craniotomy unit is used to perform layered cutting of the skull of a target animal until the dura mater is exposed, according to laser cutting parameters. The host computer is also used to control the injection execution unit to position the injection needle to the target point according to the mechanical coordinates of the target point; The injection execution unit is used to control the injection needle to puncture, administer medication, and withdraw the needle according to the injection parameters.

[0017] The beneficial effects of this invention are as follows: 1. This invention determines the laser cutting and injection parameters based on the target animal type, then acquires a top-view image of the skull to obtain the mechanical coordinates of the target point, and then controls the laser craniotomy unit to perform layered cutting to expose the dura mater. Finally, the target point coordinates are calibrated and the injection execution unit is driven to complete precise puncture, drug administration and needle withdrawal. This avoids the risk of brain displacement caused by the disconnect between the craniotomy and injection process, significantly improves the repeatability and accuracy of target point localization and drug administration, and reduces the dependence on operator experience. It is especially suitable for the needs of precise intracranial drug administration experiments in small animals such as mice.

[0018] 2. This invention utilizes a brain stereotactic mapping data model to determine the cutting area and shape, and preliminarily confirms the corresponding cutting power, cutting speed, number of cutting layers, cutting thickness, and pulse width, reducing the difficulty of setting laser cutting parameters. Simultaneously, the image acquisition unit uses four acquired marker points to confirm the mechanical coordinates of the target point, enabling the laser craniotomy unit and injection execution unit to execute corresponding actions more precisely. Furthermore, the mechanical coordinates of the target point can be recalibrated after the craniotomy operation, further improving the operational accuracy of the injection execution unit and meeting practical experimental requirements. Attached Figure Description

[0019] Figure 1 This is a flowchart illustrating the steps of the intracranial precise drug delivery method integrating craniotomy and localized injection of the present invention. Figure 2 This is a schematic diagram showing the positions of the four marker points of the present invention on the skull; Figure 3 This is a schematic diagram of the intracranial precision drug delivery system integrating craniotomy positioning and injection according to the present invention. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The components of the embodiments of the present invention described and shown in the accompanying drawings can generally be arranged and designed in various different configurations.

[0021] Therefore, the following detailed description of the embodiments of the invention provided in the accompanying drawings is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the invention without inventive effort are within the scope of protection of the invention.

[0022] It should be noted that similar labels and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures.

[0023] In the description of the embodiments of the present invention, it should be noted that if terms such as "upper," "lower," "horizontal," or "inner" indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, or the orientation or positional relationship commonly used when the product of the invention is in use, they are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the present invention. Furthermore, terms such as "first" and "second" are only used to distinguish descriptions and should not be construed as indicating or implying relative importance.

[0024] Example 1 refer to Figure 1 This invention provides a method for precise intracranial drug delivery integrating craniotomy and localized injection, comprising the following steps: S1. Determine the laser cutting parameters and injection parameters based on the target animal type; S2. Fix the target animal and acquire a top view image of the target animal's skull through the image acquisition unit to obtain the mechanical coordinates of the target point; S3. Based on the laser cutting parameters, the laser craniotomy unit is controlled to perform layered cutting of the target animal's skull until the dura mater is exposed. S4. Calibrate the mechanical coordinates of the target point and drive the injection execution unit to position the injection needle to the target point; S5. The injection execution unit controls the injection needle to puncture, administer medication, and withdraw the needle towards the target point based on injection parameters.

[0025] To further explain, step S1 includes the following steps: S1.1 Matching species and age-related strains with corresponding stereotactic brain mapping data models; Taking mice as an example, 8-week-old SPF-grade C57BL / 6 male mice weighing 22±2g were selected and input into the host computer. The host computer automatically retrieved the brain stereotaxic atlas data model of Paxinos mice of the corresponding strain and age, which also included the corresponding skull thickness and density.

[0026] S1.2 Determine the cutting region and cutting shape in the brain stereotactic mapping data model, and match the corresponding cutting power, cutting speed, number of cutting layers, cutting thickness and pulse width; Operators can draw the cutting area and shape on the stereoscopic brain mapping data model of Paxinos mice through the display terminal of the host computer. The host computer calculates and matches the corresponding cutting data based on the corresponding skull thickness and density.

[0027] Centered on the skull projection of the target point in the substantia nigra pars compacta on one side of the mouse, a circular cutting area with a diameter of 1 mm and the cutting shape were drawn. The host computer calculated and matched the cutting power of 6 W, pulse width of 20 ns, repetition frequency of 50 kHz, scanning speed of 2 mm / s, and the number of cutting layers of 10 layers, with a cutting depth of 0.05 mm. The calculated and matched cutting data can be automatically modified.

[0028] S1.3 Select target points in the brain stereotaxic mapping data model and obtain the model coordinates of the target points; Similarly, based on the Paxinos mouse brain stereotaxic atlas data model, the brain region of the target point is selected and the coordinates of the target point in the Paxinos mouse brain stereotaxic atlas data model are specified, i.e., the model coordinates of the target point. Taking the substantia nigra pars compacta of one side of the mouse as the target point as an example, the model coordinates of the target point are AP=-3.0mm, ML=1.2mm, and DV=-4.5mm. The injection angle, puncture speed, injection dose, injection speed and needle withdrawal speed are set and input into the host computer. For example, the injection angle is 90° perpendicular to the skull plane, the puncture speed is 0.3mm / s, the injection dose is 2μL, the injection speed is 0.2μL / s, and the needle withdrawal speed is 0.5mm / s.

[0029] To further explain, step S2 includes the following steps: S2.1 Fix the target animal on the workbench and adjust the head angle of the target animal so that the height difference between its anterior and posterior fontanelles is ≤0.01mm; The laser craniotomy unit and the injection execution unit are both mounted on the worktable and can be precisely controlled to move via a host computer based on the worktable's coordinate system.

[0030] Typically, after mice are anesthetized by continuous inhalation of isoflurane, the hair on the top of the skull is removed, the scalp is cut along the midline, the periosteum is bluntly dissected to fully expose the skull, and the mice are fixed on the ear rods and maxillary clamps of the stereotaxic instrument on the workbench. The height of the maxillary clamps is adjusted so that the height difference between the anterior and posterior fontanelles is ≤0.01mm, thus completing the horizontal alignment of the skull.

[0031] S2.2. Use the image acquisition unit to acquire a top view of the target animal's skull, and then use a filter to enhance the image boundaries to obtain a top view image of the target animal's skull. refer to Figure 2 A top view of the mouse skull was acquired using a CCD industrial camera, and the image boundaries were enhanced by processing with a Frangi filter to obtain the top view of the mouse skull.

[0032] S2.3 Identify the anterior and posterior fontanelle markers, as well as their two-dimensional image coordinates, based on the top-view image of the target animal's skull; Based on the OpenCV library and YOLO model, the two-dimensional spatial coordinates of two core anatomical landmarks, the anterior and posterior fontanelles, of the mouse skull were identified from a top view of the mouse skull. These coordinates are the two-dimensional image coordinates of the anterior and posterior fontanelles.

[0033] S2.4. Take the line connecting the anterior and posterior fontanelle markers as the initial longitudinal axis, and use the sagittal suture of the skull to correct the yaw error of the initial longitudinal axis to obtain a positioning longitudinal axis that coincides with the sagittal suture of the skull. S2.5. Select suture markers on the cranial bones on both sides of the positioning longitudinal axis, with a perpendicular distance X from the positioning longitudinal axis, and obtain the two-dimensional image coordinates of the two suture markers respectively. Where X is 0.5cm.

[0034] S2.6. Based on hand-eye calibration, convert the two-dimensional image coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone seam markers into corresponding two-dimensional mechanical coordinates; In the initial stage, images of multiple known points on the worktable are acquired using a CCD industrial camera, and the mapping relationship between the two-dimensional image coordinates of the points in the image and the mechanical coordinates of the same points on the worktable is obtained. Then, the two-dimensional image coordinates of the front fontanelle marker, the back fontanelle marker, and the two herringbone seam markers are converted into the two-dimensional mechanical coordinates of the front fontanelle marker, the back fontanelle marker, and the two herringbone seam markers, that is, the planar coordinates on the worktable.

[0035] S2.7. Using a vertical distance measuring instrument, obtain the vertical distances of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seam markers at the same height, and obtain the three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seam markers respectively. On the workbench, a vertical rangefinder is moved to the two-dimensional mechanical coordinate positions of the front fontanelle marker, the back fontanelle marker, and the two herringbone seam markers via a slide rail equipped with an absolute grating displacement sensor. The distances between the front fontanelle marker, the back fontanelle marker, and the two herringbone seam markers and the vertical rangefinder are obtained. A vertically downward laser rangefinder is selected as the vertical rangefinder, with a ranging accuracy of ±0.002mm.

[0036] Based on the height of the laser rangefinder on the worktable, the vertical coordinates of the front fontanelle marker, the rear fontanelle marker, and the two herringbone seam markers in the mechanical coordinate system can be obtained, and then the three-dimensional mechanical coordinates of the front fontanelle marker, the rear fontanelle marker, and the two herringbone seam markers can be obtained.

[0037] S2.8. Based on the three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone suture markers, and their three-dimensional model coordinates in the brain stereotaxic mapping data model, obtain the affine transformation matrix that maps the model coordinates to the mechanical coordinates. At this point, the three-dimensional mechanical coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone suture markers are the measured positions, while the model coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone suture markers in the brain stereotaxic mapping data model are the ideal positions. Therefore, after obtaining the affine transformation matrix, verification is required.

[0038] To further explain, step S2.8 also includes the following steps: S2.8a. Obtain the affine transformation matrix mapping the model coordinates to the machine coordinates using the ICP iterative nearest point algorithm. ; S2.8b, Calculate the affine transformation matrix error :

[0039] in, This represents the number of marked points; in this case, N=4. For the first Model coordinates of each marker point For the first The mechanical coordinates of each marker point; S2.8c, Determine the affine transformation matrix error Check if the mapping error is satisfied; if yes, end the process; otherwise, re-obtain the affine transformation matrix. The mapping error is maintained until the mapping error is satisfied; where the mapping error is 0.03mm.

[0040] S2.9. Based on the affine transformation matrix, convert the model coordinates of the target point into the mechanical coordinates of the target point.

[0041] To further explain, step S3 includes the following steps: S3.1. Based on the mapping relationship, determine the cutting path of the laser craniotomy unit according to the cutting shape in the brain stereotactic mapping data model; The host computer converts the model coordinates of the cutting shape contour in the brain stereoscopic localization atlas data model into mechanical coordinates, thus obtaining the continuous mechanical coordinates of the cutting path of the laser craniotomy unit during the cutting process.

[0042] S3.2 The laser craniotomy unit operates at low power along the cutting path. By optimizing the cutting path, the deviation between the current cutting area and the target cutting area meets the cutting error. To avoid cutting failure due to deviations in the cutting area, a cutting power of 1W can be used to irradiate along the cutting path to obtain irradiation marks. Therefore, the cutting error between the irradiation marks and the actual cutting area can be determined. If so, continue; otherwise, optimize and adjust the cutting path and re-execute step S3.2.

[0043] S3.3 Activate the laser craniotomy unit and perform layered cutting of the target animal's skull according to the determined laser cutting parameters until the dura mater is exposed; Once the cutting path is determined, the host computer controls the laser craniotomy unit to perform layered cutting along the cutting path.

[0044] During the cutting process, a downward-facing laser rangefinder can be fitted onto the outside of the laser head to obtain the current height of the skull surface in real time. This allows for dynamic adjustment of the laser galvanometer height for laser focusing, keeping the laser focus at the cutting position. The laser rangefinder collects the skull surface height in real time at a frequency of 100Hz, with a focusing compensation accuracy of ±0.003mm.

[0045] Because the cutting process is easily affected by external environmental factors, errors can occur during laser cutting. Therefore, real-time monitoring is required during the cutting process to optimize and adjust the cutting path and cutting parameters in a timely manner, ensuring that the cutting task is completed accurately and reliably.

[0046] To further explain, step S3.3 includes the following steps: S3.3a. The top view of the skull cutting is acquired in real time through the image acquisition unit, and the laser cutting boundary is obtained by using the Hessian matrix and the Frangi filter to obtain the top view of the skull cutting. During the cutting process, the host computer drives the image acquisition unit to move above the skull to obtain a top view of the skull cutting in real time. Then, the host computer obtains the laser cutting boundary through the Hessian matrix and the Frangi filter, which facilitates the comparison between the obtained laser cutting boundary and the planned cutting path.

[0047] S3.3b. Adjust the cutting path in real time according to the deviation between the laser cutting boundary and the target cutting path; The host computer adjusts the cutting path based on the magnitude and direction of the deviation between the current cutting position and the position on the target cutting path, thus completing the micron-level dynamic calibration of the cutting contour.

[0048] S3.3c. After each layer of the skull is cut, the remaining skull thickness is obtained using a vertical rangefinder. After completing the k-th layer cut, the actual remaining skull thickness after the k-th layer cut can be obtained using the skull thickness and digital display rangefinder. Since the theoretical cutting depth is 0.05mm per layer, the theoretical remaining skull thickness after the k-th layer cut can be obtained from the host computer based on the skull thickness. At this point, the cutting error of the current layer is calculated. :

[0049] in, This represents the theoretical remaining skull thickness after the current k-th layer is cut. This represents the actual remaining skull thickness after the current k-th layer is cut. when When the theoretical remaining skull thickness after cutting is greater than the actual remaining skull thickness, it means that the actual cutting depth is less than the theoretical cutting depth. In this case, the cutting power of the next layer is increased and the cutting speed is reduced to increase the cutting depth. when When the actual cutting depth is greater than the theoretical cutting depth, the cutting power of the next layer is reduced and the cutting speed is increased to reduce the cutting thickness and avoid cutting through.

[0050] S3.3d: Optimize the cutting power and cutting speed according to the remaining skull thickness until the last layer of skull is cut.

[0051] S3.4. Turn off the laser craniotomy unit.

[0052] During the cutting process, when the actual remaining skull thickness reaches the preset craniotomy depth and the error is within ±0.005mm, the host computer determines that the cutting is complete, shuts down the laser craniotomy unit, and fully exposes the dura mater.

[0053] To further explain, step S4 includes the following steps: S4.1. Use the image acquisition unit and vertical rangefinder to reacquire the three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seams, and determine whether they exceed the offset error. If so, redetermine the mechanical coordinates of the target point. After the cutting was completed, the dura mater was confirmed to be intact and without bleeding using a CCD industrial camera. Then, the current two-dimensional image coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone sutures were re-acquired using the CCD industrial camera and converted into the current two-dimensional mechanical coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone sutures. Finally, the current three-dimensional mechanical coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone sutures were obtained using a vertical rangefinder.

[0054] The offset error is calculated based on the current three-dimensional mechanical coordinates and the three-dimensional mechanical coordinates obtained in step S2.7. The offset error is ±0.01mm. If it does not exceed the offset error, continue. If it exceeds the offset error, the mechanical coordinates of the target point need to be re-determined according to steps S2.2~S2.7 to calibrate the mechanical coordinates of the target point and ensure that the accuracy is ≤±0.01mm.

[0055] S4.2. Based on the determined mechanical coordinates of the target point, control the injection execution unit to move the injection needle directly above the target point; Based on the current mechanical coordinates of the target point, the host computer controls the injection execution unit to move on the worktable, so that the tip of the injection needle moves above the center projection position of the target bone window. The movement accuracy of the injection needle is ≤ ±0.003mm, the repeatability is ≤ ±0.002mm, and the deviation between the tip of the injection needle and the center projection position of the target bone window is ≤ ±0.01mm.

[0056] To further explain, step S5 includes the following steps: S5.1 Control the injection needle to puncture the target point mechanical coordinates along the set injection angle and set puncture speed; The host computer controls the injection needle to move continuously at a speed of 0.3 mm / s in the corresponding direction according to the set injection angle and puncture speed, until the needle tip moves to a depth of DV=-4.5 mm.

[0057] A force sensor can be optionally installed on the tip of the injection needle. During the movement of the injection needle, when the resistance exceeds the limit, the feed will stop and an early warning will be issued. Optionally, the force sensor sampling frequency is ≥100Hz, the range is 0-200mN, and the resistance over-limit value is 50mN.

[0058] S5.2. Control the injection to deliver the drug to the target point according to the set injection dose and injection speed; Once the injection needle reaches the target location, preparations are made to begin administering the medication.

[0059] Specifically, the micro-injection drive mechanism injects 2 μL of drug at a uniform rate of 0.2 μL / s, with an injection resolution ≤0.005 μL and a dosage error ≤±0.01 μL.

[0060] S5.3 The injection execution unit controls the injection needle to complete the withdrawal according to the set needle withdrawal speed; After drug administration, based on the requirements of leakage prevention and safety monitoring, the host computer executes a leakage prevention control program that includes in-situ dwell, micro-withdrawal, and secondary dwell to balance the needle channel pressure and prevent drug leakage.

[0061] Specifically, after the drug is administered, the injection needle remains in place for 5 seconds, then is precisely withdrawn by 0.1 mm, and then remains in place for another 30 seconds to complete the needle pressure compensation.

[0062] Subsequently, the image acquisition unit, laser craniotomy unit, and injection execution unit are all reset. The host computer can then choose to store the entire experimental data and operation log, and end the experiment.

[0063] Example 2 refer to Figure 3 This embodiment provides an integrated intracranial precision drug delivery system with craniotomy positioning and injection, used to implement the integrated intracranial precision drug delivery method with craniotomy positioning and injection provided in this embodiment, including: The image acquisition unit is used to acquire a top-view image of the skull of a fixed target animal; The host computer is used to obtain the mechanical coordinates of the target point based on the acquired top view image of the skull, and is used to calibrate the mechanical coordinates of the target point. The laser craniotomy unit is used to perform layered cutting of the skull of a target animal until the dura mater is exposed, according to laser cutting parameters. The host computer is also used to control the injection execution unit to position the injection needle to the target point according to the mechanical coordinates of the target point; The injection execution unit is used to control the injection needle to puncture, administer medication, and withdraw the needle according to the injection parameters.

[0064] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered illustrative and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the scope of the invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0065] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can be appropriately combined to form other embodiments that can be understood by those skilled in the art. The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

[0066] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for precise intracranial drug delivery integrating craniotomy, localization, and injection, characterized in that, Includes the following steps: Based on the target animal type, determine the laser cutting parameters and injection parameters; The target animal is fixed in place, and a top-view image of the target animal's skull is acquired through the image acquisition unit to obtain the mechanical coordinates of the target point; The laser craniotomy unit, controlled by laser cutting parameters, performs layered cutting of the target animal's skull until the dura mater is exposed. The mechanical coordinates of the target point are calibrated, and the injection execution unit is driven to position the injection needle to the target point. The injection execution unit controls the injection needle to puncture, administer medication, and withdraw the needle towards the target site based on injection parameters.

2. The integrated intracranial precise drug delivery method with craniotomy positioning and injection as described in claim 1, characterized in that, The determination of laser cutting and injection parameters based on the target animal type includes the following steps: Match the corresponding stereotaxic atlas data model to the target animal species and age strain; In the brain stereotactic mapping data model, the cutting region and cutting shape are determined, and the corresponding cutting power, cutting speed, number of cutting layers, cutting thickness and pulse width are matched. Select target points in the brain stereotaxic mapping data model and obtain the model coordinates of the target points; Set the injection angle, puncture speed, injection dose, injection speed, and needle withdrawal speed.

3. The integrated intracranial precise drug delivery method with craniotomy positioning and injection as described in claim 2, characterized in that, The process of acquiring a top-view image of the target animal's skull using an image acquisition unit to obtain the mechanical coordinates of the target point includes the following steps: Fix the target animal on the workbench and adjust the angle of the target animal's head so that the height difference between its anterior and posterior fontanelles is ≤0.01mm; The image acquisition unit acquires a top view of the target animal's skull, and the image boundary is enhanced by a filter to obtain a top view image of the target animal's skull. Identify the anterior and posterior fontanelle markers, as well as their two-dimensional image coordinates, based on a top-view image of the target animal's skull; The line connecting the anterior and posterior fontanelle markers is used as the initial longitudinal axis. The yaw error of the initial longitudinal axis is corrected by the sagittal suture of the skull to obtain a positioning longitudinal axis that coincides with the sagittal suture of the skull. On the cranial sutures on both sides of the positioning longitudinal axis, select suture markers with a perpendicular distance X from the positioning longitudinal axis, and obtain the two-dimensional image coordinates of the two suture markers respectively; Based on hand-eye calibration, the two-dimensional image coordinates of the anterior fontanelle marker, posterior fontanelle marker, and two herringbone seam markers are converted into corresponding two-dimensional mechanical coordinates; Using a vertical rangefinder, the vertical distances of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seam markers were obtained at the same height, and the three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seam markers were obtained respectively. Based on the three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone suture markers, and their three-dimensional model coordinates in the brain stereotaxic mapping data model, the affine transformation matrix mapping the model coordinates to the mechanical coordinates is obtained. Based on the affine transformation matrix, the model coordinates of the target point are converted into the mechanical coordinates of the target point.

4. The integrated intracranial precise drug delivery method with craniotomy positioning and injection as described in claim 3, characterized in that, Obtaining the affine transformation matrix mapping the model coordinates to the machine coordinates includes the following steps: The affine transformation matrix mapping the model coordinates to the machine coordinates is obtained through the ICP iterative nearest point algorithm. ; Calculate the affine transformation matrix error : in, The number of markers, For the first Model coordinates of each marker point For the first The mechanical coordinates of each marker point; Determine the affine transformation matrix error Check if the mapping error is satisfied; if yes, end the process; otherwise, re-obtain the affine transformation matrix. Continue until the mapping error is satisfied.

5. The integrated intracranial precise drug delivery method with craniotomy positioning and injection according to claim 3, characterized in that, The laser craniotomy unit, controlled by laser cutting parameters, performs layered cutting of the target animal's skull to expose the dura mater, including the following steps: Based on the mapping relationship, the cutting path of the laser craniotomy unit is determined according to the cutting shape in the brain stereotactic mapping data model. The laser craniotomy unit operates at low power along the cutting path. By optimizing the cutting path, the deviation between the current cutting area and the target cutting area meets the cutting error. The laser craniotomy unit is activated, and the target animal's skull is cut layer by layer according to the determined laser cutting parameters until the dura mater is exposed. Turn off the laser craniotomy unit.

6. The integrated intracranial precise drug delivery method with craniotomy positioning and injection as described in claim 5, characterized in that, The process of performing layered cutting of the target animal skull according to the determined laser cutting parameters includes the following steps: The top view of the skull cutting is acquired in real time by the image acquisition unit, and the laser cutting boundary is obtained by using the Hessian matrix and the Frangi filter on the top view of the skull cutting. The top view of the skull cut is used to obtain the laser cutting boundary through a Hessian matrix and a Frangi filter. The cutting path is adjusted in real time based on the deviation between the laser cutting boundary and the target cutting path; After each layer of the skull is cut, the remaining skull thickness is obtained using a vertical rangefinder; The cutting power and speed are optimized based on the remaining skull thickness until the last layer of skull is cut.

7. The integrated intracranial precise drug delivery method with craniotomy positioning and injection as described in claim 6, characterized in that, The optimization of cutting power and cutting speed based on the remaining skull thickness includes the following steps: Calculate the cutting error of the current layer : in, This represents the theoretical remaining skull thickness after the current k-th layer is cut. This represents the actual remaining skull thickness after the current k-th layer is cut. when At the same time, increase the cutting power of the next layer and reduce the cutting speed; when At this time, reduce the cutting power of the next layer and increase the cutting speed.

8. The integrated intracranial precise drug delivery method with craniotomy positioning and injection according to claim 3, characterized in that, The process of calibrating the mechanical coordinates of the target point and driving the injection execution unit to position the injection needle to the target point includes the following steps: The three-dimensional mechanical coordinates of the anterior fontanelle marker, the posterior fontanelle marker, and the two herringbone seams are re-acquired using the image acquisition unit and the vertical rangefinder, and it is determined whether the offset error is exceeded. If so, the mechanical coordinates of the target point are re-determined. Based on the determined mechanical coordinates of the target point, the injection execution unit is controlled to move the injection needle directly above the target point.

9. The integrated intracranial precise drug delivery method with craniotomy positioning and injection as described in claim 8, characterized in that, The injection execution unit controls the injection needle to puncture, administer medication, and withdraw the needle towards the target point based on injection parameters, including the following steps: The injection needle is controlled to penetrate the target point at a set injection angle and puncture speed. The injection is controlled to deliver the drug to the target site according to the set injection dose and injection speed. The injection execution unit controls the injection needle to complete the withdrawal according to the set withdrawal speed.

10. A craniotomy-guided, localized, and precise intracranial drug delivery system, characterized in that, The method for implementing the integrated intracranial precise drug delivery method with craniotomy positioning and injection as described in any one of claims 1 to 9 includes: The image acquisition unit is used to acquire a top-view image of the skull of a fixed target animal; The host computer is used to obtain the mechanical coordinates of the target point based on the acquired top view image of the skull, and is used to calibrate the mechanical coordinates of the target point. The laser craniotomy unit is used to perform layered cutting of the skull of a target animal until the dura mater is exposed, according to laser cutting parameters. The host computer is also used to control the injection execution unit to position the injection needle to the target point based on the mechanical coordinates of the target point; The injection execution unit is used to control the injection needle to puncture, administer medication, and withdraw the needle according to the injection parameters.

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