Convection-based enhanced drug delivery catheter assembly, drug delivery system, and method of use

Abstract

The invention provides a catheter assembly based on convection enhanced drug delivery, a drug delivery system and a using method.The catheter assembly comprises an outer sleeve and an inner sleeve which are coaxially arranged in a composite mode, and the catheter assembly sequentially comprises a catheter tip section, a rigid supporting section and a shearing buffering section from the far end to the near end; at the tip section of the catheter, the inner sleeve extends out of the far end of the outer sleeve and is coaxially fixed with the outer sleeve in cooperation with a conical connecting piece, and the length of the part, extending out of the far end, of the inner sleeve ranges from 0.8 cm to 1.2 cm; in the rigid supporting section, the outer sleeve wraps the inner sleeve; in the shearing buffering section, the inner sleeve extends out of the near end of the outer sleeve, an inner channel of the shearing buffering section is communicated with an inner cavity of the catheter tip section, and the shearing buffering section is configured to be in butt joint with an infusion pipeline through a connecting piece after being sheared. Through innovative material combination and precise parameterized structural design, countercurrent can be effectively inhibited, image interference is reduced, and safety, effectiveness and controllability of intracranial local drug delivery treatment are remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to a catheter assembly, a drug delivery system, and a corresponding method of use for convection-enhanced drug delivery (CED). Background Technology

[0002] Drug treatment for intracranial or central nervous system diseases has long faced a fundamental challenge: therapeutic drugs need to cross multiple physiological barriers and achieve and maintain sufficient and spatially relatively uniform effective concentrations in the target lesion area.

[0003] The blood-brain barrier (BBB) ​​is composed of tight junctions of brain capillary endothelial cells, the basement membrane, and astrocyte foot processes, forming a highly selective blood-brain interface that strictly restricts the entry of macromolecules, hydrophilic small molecules, and charged molecules into the brain parenchyma.

[0004] Therefore, systemic drug delivery often fails to achieve ideal local exposure in brain tissue, and also faces problems such as side effects caused by systemic distribution, rapid metabolic clearance, and difficulty in maintaining effective concentrations in the brain.

[0005] To bypass the blood-brain barrier and improve target exposure, researchers have proposed various intracranial / central nervous system local drug delivery strategies. Typical protocols include: Intraventricular drug delivery / Ommaya reservoir: A reservoir connected to the ventricles is surgically implanted, and drugs are injected into the ventricles percutaneously. Drug distribution relies on cerebrospinal fluid circulation. However, drug penetration from the ventricles into the brain parenchyma is extremely inefficient, mainly limited to the ventricles and subarachnoid surfaces, offering limited efficacy against intraparenchymal lesions and posing risks of infection, blockage, and reflux.

[0006] Intrathecal injection in the lumbar spine: The drug is injected into the subarachnoid space of the spinal cord, where it diffuses upwards into the intracranial space via the flow of cerebrospinal fluid. This method also faces the problem of the drug's ineffective entry into the brain parenchyma, and the distribution of the drug is uncontrollable, making it difficult to maintain a consistent concentration.

[0007] Local implantation / sustained-release agents during craniotomy: During craniotomy, drugs or biodegradable sustained-release materials (such as polymer sheets containing chemotherapy drugs) are placed directly into the tumor resection cavity or around the lesion. Although this method can achieve high local concentrations, the drug release kinetics are uncontrollable, the distribution range is extremely limited (usually only a few millimeters around the implantation point), and it may cause complications such as local inflammation and adhesions.

[0008] Convection-enhanced delivery (CED) is a pressure-driven local drug delivery technique.

[0009] Its basic principle is to implant a microcatheter into the target area of ​​the brain parenchyma and establish a stable pressure gradient through an external micro-injection pump, so that the drug solution generates convection in the interstitial space, thereby actively promoting the spatial distribution of the drug in the brain tissue.

[0010] Compared to local injection that relies solely on molecular diffusion, CED can significantly reduce diffusion distance limitations, enabling macromolecular drugs, antibodies, drug-loaded nanoparticles, and other substances to achieve wider and relatively uniform coverage within brain tissue, theoretically achieving centimeter-level distribution.

[0011] Despite the promising future of CED technology, its translation from the laboratory to the clinic faces numerous severe technical challenges, primarily stemming from the design, materials, and compatibility of the catheter itself with clinical practice. Reflux problem: This is one of the most common and challenging technical bottlenecks in CED.

[0012] The term "backflow" refers to the situation where the drug solution fails to penetrate and expand primarily into the tissue ahead, but instead flows back towards the proximal end along the low-resistance channel between the outer wall of the duct and the tissue.

[0013] Backflow can lead to two consequences: first, the effective dose and distribution volume in the target area decrease, affecting the therapeutic effect; second, the drug entering the non-target area may cause toxicity or complications.

[0014] The occurrence of backflow is closely related to the geometry and size of the catheter tip, the coaxiality of the inner and outer tubes, the infusion rate and pressure, and the heterogeneity of brain tissue (such as tumor necrosis areas, blood vessels, fiber bundle orientation, etc.).

[0015] Limitations of catheter materials and structure: Early CED catheters were mostly made of metal materials such as stainless steel. Although they were rigid enough and easy to implant, they were prone to producing significant artifacts under magnetic resonance imaging (MRI) or computed tomography (CT) scans, affecting catheter tip positioning and drug distribution assessment.

[0016] Some polymer catheters (such as polyurethane and silicone) have improved imaging compatibility, but their mechanical strength, fatigue resistance, long-term indwelling durability, and performance stability after repeated sterilization are often insufficient.

[0017] In addition, the solution of using multi-port silicon-based catheters to reduce local pressure may still have problems such as high material brittleness, easy breakage, complex manufacturing process, high cost, and fixed length and port position, making it difficult to adapt to individualized surgical needs.

[0018] Poor intraoperative adaptability: Most existing CED catheters are designed with a fixed length, while the lesion depth, anatomical structure and surgical approach angle vary significantly among different patients.

[0019] When the preset length of the catheter does not match the actual access distance, it is often necessary to replace the catheter with one of different lengths, adjust the puncture path, or repeat the puncture in clinical practice.

[0020] The above procedures not only increase surgical time and the complexity of instrument preparation, but also increase the risk of tissue trauma and bleeding, and may affect the final drug distribution effect due to positioning errors.

[0021] Lack of real-time monitoring and feedback means: the traditional CED infusion process is largely a "blind operation".

[0022] After doctors set the flow rate, total amount, and time, it is difficult to know in a timely manner the actual distribution of the drug in the brain tissue, the leading edge position, and whether backflow occurs.

[0023] The results can usually only be assessed by imaging follow-up (such as MRI) after infusion. Once problems such as insufficient distribution or reflux are found, it is often difficult to remedy the situation in the same treatment.

[0024] The lack of real-time visualization and quantitative feedback limits the accuracy, safety, and repeatability of CED treatment.

[0025] In summary, existing CED drug delivery devices or strategies still have significant shortcomings in areas such as backflow control, material and structural compatibility, intraoperative individualized adaptation, and real-time monitoring and quantitative assessment of the infusion process. Therefore, it is necessary to provide a novel CED catheter assembly, drug delivery system, and method of use to systematically improve the safety, efficacy, and controllability of intracranial local drug delivery. Summary of the Invention

[0026] To address the problems in the prior art, the present invention aims to provide a catheter assembly, drug delivery system, and method of use based on convection-enhanced drug delivery, which overcomes the difficulties of the prior art and can effectively suppress backflow, reduce image interference, and significantly improve the safety, effectiveness, and controllability of intracranial local drug delivery therapy through innovative material combinations and precise parametric structural design.

[0027] This invention provides a catheter assembly based on convection-enhanced drug delivery, comprising: The catheter assembly comprises an outer sheath and an inner sheath arranged coaxially. From distal to proximal, the catheter assembly includes a catheter tip section, a rigid support section, and a shearable buffer section. At the catheter tip section, the inner sheath extends from the distal end of the outer sheath and is coaxially fixed with the outer sheath using a tapered connector. The length of the inner sheath extending beyond the distal end is L, and the length L ranges from 0.8 cm to 1.2 cm. In the rigid support section, the outer sleeve covers the inner sleeve; In the shearable buffer section, the inner cannula extends from the proximal end of the outer cannula, the inner channel of the shearable buffer section communicates with the inner lumen of the catheter tip section, and the shearable buffer section is configured to connect to the infusion line via a connector after being sheared.

[0028] Preferably, the outer sheath is made of zirconium oxide ceramic containing 3 molar percentage of yttrium oxide.

[0029] Preferably, the outer tube has a density ≥99%, a grain size of 0.2μm to 0.6μm, a bending strength ≥900 MPa, and a fracture toughness ≥6 MPa·m^1 / 2.

[0030] Preferably, the outer diameter of the outer sleeve is 1.6 mm to 2.4 mm, the inner diameter is 0.80 mm to 1.10 mm, and the surface roughness of the inner wall is Ra ≤ 0.2 μm.

[0031] Preferably, the distal outer wall of the outer sleeve is further processed with an anti-backflow geometry, which is selected from one or more combinations of micro-step structure, concave step structure, pressure reducing cavity structure and sealing ring structure.

[0032] Preferably, the inner sheath is a medical-grade polyetheretherketone microcatheter, which is annealed at 250°C to 300°C for 1 to 2 hours after extrusion molding, and then slowly cooled at a rate of 0.5°C to 1°C per hour to eliminate internal stress.

[0033] Preferably, the outer wall of the shearable buffer section is prefabricated with an annular graduated groove for indicating the cutting position.

[0034] Preferably, the connector is a locking joint, and the shearable buffer section is connected to the infusion line and the scalp anchoring device through the locking joint. The infusion line is a rubber hose, and the locking joint is provided with a sealing ring and a thrust ring. The leakage of the locking joint under a static pressure of 0.2 MPa is ≤0.01 ml / min, and the pull-out force is ≥20 N.

[0035] Preferably, the outer diameter of the inner sleeve and the inner diameter of the outer sleeve are in an interference or transition fit, with the interference or transition amount being ±5μm to ±30μm.

[0036] Preferably, the inner sleeve and the outer sleeve are thermally fitted together. The inner sleeve is heated to 120 to 150 degrees Celsius and then inserted into the inner hole of the outer sleeve at room temperature. After cooling, the inner sleeve shrinks to form a tight fit with the inner wall of the outer sleeve.

[0037] Preferably, the flow rate at the tip of the catheter is in the range of 0.5 μL / min to 3.0 μL / min, so that the pressure drop in the injected tissue is smoothly distributed radially and the drug flow front expands in a quasi-spherical shape.

[0038] The present invention also provides an intracranial drug delivery system, employing the above-described convection-enhanced drug delivery catheter assembly, and further comprising: An injection pump is connected to the infusion tubing; An image navigation device integrated module includes a positioning adapter component and a neurosurgical navigation device. One end of the positioning adapter component clamps the convection-enhanced drug delivery catheter assembly, and the other end is connected to the neurosurgical navigation device. At least a portion of the outer sheath serves as an imaging reference area. The outer periphery or inner wall of the imaging reference area is provided with a marker pattern that can be recognized by an optical navigation system or an electromagnetic navigation system. The neurosurgical navigation device drives the positioning adapter component to navigate the convection-enhanced drug delivery catheter assembly based on detecting the position of the imaging reference area.

[0039] Preferably, it further includes: Magnetic resonance imaging equipment generates T1-weighted magnetic resonance images; The drug distribution quantitative monitoring module is based on a pre-established quantitative relationship model between magnetic resonance T1 relaxation rate and contrast agent Gd-DTPA concentration. By acquiring magnetic resonance T1-weighted images of brain parenchyma during or after infusion, the module calculates the T1 relaxation time of each voxel and inversely calculates the Gd-DTPA concentration of the corresponding voxel, thereby generating a spatial distribution map of drug concentration to quantitatively assess drug distribution volume, the ratio of distribution volume to infusion volume, and backflow-related parameters. The drug distribution quantitative monitoring module is communicatively connected to the infusion pump control system to form a closed-loop control loop, enabling the infusion pump control system to dynamically adjust the infusion pump flow rate, infusion volume, or pause infusion based on the real-time monitored drug concentration distribution map.

[0040] Preferably, it further includes: a data processing unit, which is connected to the infusion pump, the image navigation device integration module, the magnetic resonance imaging device, and the drug distribution quantitative monitoring module, respectively. The data processing unit is configured to execute the drug distribution quantitative monitoring algorithm and visualize the operating parameters and monitoring results.

[0041] The present invention also provides an intracranial drug delivery method, which uses the above-mentioned intracranial drug delivery system, and cuts the shearable buffer section of the convection-enhanced drug delivery catheter assembly according to the access distance measured by the neurosurgical navigation device during the operation, and connects the cut shearable buffer section to the infusion tubing through the connector.

[0042] Compared with the prior art, the present invention has at least the following beneficial effects (which can be combined to achieve them without contradiction): Exceptional and robust anti-backflow performance: Through the scientifically optimized tip extension length (0.8-1.2 cm), the initial flow field after drug flow is fundamentally improved. Combined with optional auxiliary geometric structures such as the distal microstep of the outer sheath, backflow can be effectively suppressed within a wide clinical flow rate range of 0.5-3.0 µL / min, ensuring efficient penetration of the drug into the anterior tissue and achieving a larger and more uniform distribution volume.

[0043] A high-performance material system: The combination of zirconia ceramics and polyetheretherketone (PEEK) combines rigidity and flexibility, unprecedentedly meeting multiple stringent requirements such as high strength, high toughness, corrosion resistance, fatigue resistance, excellent long-term biocompatibility, repeated sterilization and disinfection, and excellent MRI / CT image compatibility, providing an ideal carrier for clinical scenarios involving long-term placement and multiple treatments.

[0044] Unprecedented intraoperative flexibility: The innovative shearable and quick-reconnect design breaks the limitations of fixed-length catheters. Surgeons can tailor the catheter to each patient's unique anatomy, quickly customizing the catheter length on the operating table, greatly simplifying the surgical procedure and reducing the variety of instruments in stock and patient trauma.

[0045] Submillimeter-level precision implantation and positioning: Seamless integration with the neuronavigation system, combined with the catheter's low artifact characteristics, enables precise catheter planning and real-time guided implantation, as well as clear confirmation of postoperative position, laying a reliable spatial benchmark for repeated drug administration and efficacy evaluation.

[0046] Revolutionary visualization and quantification of the treatment process: The integrated surrogate imaging quantitative monitoring module transforms the CED from a "black box" operation into a "transparent" process. Real-time, quantitative, and three-dimensional drug distribution information provides physicians with powerful decision support tools, enabling dynamic optimization of treatment parameters based on individual responses, significantly improving the controllability, predictability, and success rate of treatment.

[0047] Extensive application potential: This catheter system is not only suitable for CED delivery of traditional drugs such as small molecule chemotherapy drugs, protein antibodies, and nucleic acid drugs, but its gentle convection pressure is also particularly suitable for in vivo delivery of cell therapy agents (such as tumor-infiltrating lymphocytes, neural stem cells, and CAR-T cells), improving cell survival and distribution. Animal experiments have even shown that CED infusion buffer alone can alter the tumor immune microenvironment, providing new insights for combination therapy with immune checkpoint inhibitors. Furthermore, based on the excellent heat resistance of zirconium oxide, micro-heating elements can be easily integrated in the future to achieve synergistic effects between local hyperthermia and chemotherapy / immunotherapy.

[0048] The convection-enhanced drug delivery catheter assembly, drug delivery system, and method of use of the present invention can systematically solve the bottleneck problems faced by traditional CED technology, such as difficulty in backflow control, large image interference, poor intraoperative flexibility, and lack of process visualization, through innovative material combinations, precise parametric structural design, and multifunctional module integration. This significantly improves the safety, effectiveness, and controllability of intracranial local drug delivery therapy. Attached Figure Description

[0049] Other features, objects, and advantages of the invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings.

[0050] Figure 1 This is an exploded view of the convection-enhanced drug delivery assembly of the present invention.

[0051] Figure 2 This is a perspective view of the convection-enhanced drug delivery catheter assembly of the present invention.

[0052] Figure 3 This is a graph showing the change in drug distribution volume over time under different catheter tip lengths, as measured in the experiment.

[0053] Figure 4 This is a schematic diagram illustrating the integration of the catheter and neurosurgical navigation device of the present invention.

[0054] Figure 5 This is a schematic diagram illustrating the principle and mathematical model for calculating the Gd-DTPA concentration distribution based on magnetic resonance T1 relaxation rate inversion in this invention.

[0055] Figure 6 This image shows a comparison of staining results between the convection-enhanced drug delivery catheter assembly of this invention and other subcutaneous injection tools in a rat orthotopic glioma model.

[0056] Figure 7 Immunohistochemical staining comparison and magnified view of the effect of CED infusion of PBS using the convection-enhanced drug delivery catheter assembly of the present invention on promoting CD3-positive T cell infiltration in the tumor microenvironment, compared with the conventional local drug delivery and untreated group.

[0057] Figure 8 A graph illustrating the efficacy evaluation of CED local delivery of PD-1 antibody for the treatment of mouse GL261 glioma using the convection-enhanced drug delivery catheter assembly of the present invention.

[0058] Figure Labels Detailed Implementation

[0059] The following specific examples illustrate the implementation methods of this application. Those skilled in the art can easily understand the other advantages and effects of this application from the content disclosed herein. This application can also be implemented or applied through other different specific embodiments, and various details in this application can be modified or changed according to different viewpoints and application systems without departing from the spirit of this application. It should be noted that, unless otherwise specified, the embodiments and features in the embodiments of this application can be combined with each other.

[0060] The embodiments of this application will now be described in detail with reference to the accompanying drawings, so that those skilled in the art can easily implement the application. This application may be embodied in many different forms and is not limited to the embodiments described herein.

[0061] In this application, the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics represented in connection with that embodiment or example, which are included in at least one embodiment or example of this application. Furthermore, the specific features, structures, materials, or characteristics represented may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate different embodiments or examples represented in this application, as well as features of different embodiments or examples.

[0062] Furthermore, the terms "first" and "second" are used for illustrative purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the representation of this application, "multiple" means two or more, unless otherwise explicitly specified.

[0063] For the purpose of clearly describing this application, devices that are not relevant to the description are omitted, and the same or similar components throughout the specification are given the same reference numerals.

[0064] Throughout this specification, when it is said that a device is "connected" to another device, this includes not only "direct connection" but also "indirect connection" by placing other components in between. Furthermore, when it is said that a device "comprises" a certain constituent element, unless otherwise stated otherwise, this does not exclude other constituent elements, but rather implies that other constituent elements may be included.

[0065] When we say that a device is "above" another device, this can mean that it is directly above the other device, or it can mean that other devices are present in between. Conversely, when we say that a device is "directly" "above" another device, there are no other devices present in between.

[0066] Although the terms first, second, etc., are used in some instances herein to refer to various elements, these elements should not be limited by these terms. These terms are used only to distinguish one element from another. For example, first interface and second interface, etc., are used. Furthermore, as used herein, the singular forms “a,” “an,” and “the” are intended to also include the plural forms unless the context indicates otherwise. It should be further understood that the terms “comprising,” “including,” indicate the presence of features, steps, operations, elements, components, items, kinds, and / or groups, but do not exclude the presence, occurrence, or addition of one or more other features, steps, operations, elements, components, items, kinds, and / or groups. The terms “or” and “and / or” as used herein are interpreted as inclusive, or mean any one or any combination thereof. Thus, “A, B, or C” or “A, B, and / or C” means “any one of: A; B; C; A and B; A and C; B and C; A, B, and C.” Exceptions to this definition will only occur if the combination of elements, functions, steps, or operations is inherently mutually exclusive in some way.

[0067] The technical terms used herein are for reference only to specific embodiments and are not intended to limit the scope of this application. The singular form used herein includes the plural form unless the statement explicitly indicates otherwise. The word "comprising" as used in the specification means to specify a particular characteristic, region, integer, step, operation, element, and / or component, and does not exclude the presence or addition of other characteristics, regions, integers, steps, operations, elements, and / or components.

[0068] Although not explicitly defined, all terms, including technical and scientific terms used herein, shall have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. Terms defined in commonly used dictionaries shall be further interpreted as having a meaning consistent with the relevant technical literature and the content of this present application, and shall not be over-interpreted as having an ideal or overly formulaic meaning unless otherwise defined.

[0069] As mentioned in the background section, traditional CED catheters still face many technical bottlenecks in clinical applications: backflow problems, limitations in catheter materials and structures, poor intraoperative compatibility, and (4) a lack of real-time monitoring and quantitative assessment methods. Therefore, there is an urgent need in this field to develop a new type of CED catheter system that simultaneously addresses the following key issues: (1) Effectively suppress backflow within a wide flow rate range to ensure efficient forward delivery of the drug solution.

[0070] (2) The catheter material must have excellent mechanical properties (strength, toughness), long-term biocompatibility and stability, and excellent medical imaging compatibility (especially low MRI artifacts).

[0071] (3) The design should allow for rapid and flexible size adjustments during surgery based on the patient’s individual anatomical structure.

[0072] (4) It can be deeply integrated with existing neurosurgical navigation technology and medical imaging technology to achieve real-time, quantitative visualization monitoring of the precise implantation and infusion process, thereby providing decision support for doctors and realizing personalized and precise intracranial drug treatment.

[0073] Figure 1 This is an exploded view of the convection-enhanced drug delivery assembly of the present invention. Figure 2 This is a perspective view of the convection-enhanced drug delivery catheter assembly of the present invention. Figure 1 and 2 As shown, this invention provides a catheter assembly based on convection-enhanced drug delivery (CED), comprising: an outer cannula 2 and an inner cannula 1 coaxially coupled together. The catheter assembly, from distal to proximal, sequentially includes a catheter tip segment, a rigid support segment, and a shearable buffer segment. In the catheter tip segment, the inner cannula 1 extends from the distal end 21 of the outer cannula 2 and is coaxially fixed to the outer cannula 2 with a tapered connector 5. The length of the inner cannula 1 extending from the distal end 21 is L, ranging from 0.8 cm to 1.2 cm, used to form a stable drug release front within the tissue and reduce the risk of backflow. In the rigid support segment, the outer cannula 2 covers the inner cannula 1, providing implantation support, ensuring coaxiality and positional stability, and serving as a navigation / imaging reference area. In the shearable buffer segment, the inner cannula 1 extends from the proximal end 22 of the outer cannula 2, its internal channel communicating with the lumen of the catheter tip segment; this segment is configured to be sheared intraoperatively according to the access distance, and after shearing, it is connected to the infusion tubing 3 via a connector, achieving individualized length and rapid reconnection. This invention systematically solves the bottleneck problems faced by traditional CED technology, such as difficulty in backflow control, large image interference, poor intraoperative flexibility, and lack of process visualization, through innovative material combination, precise parametric structural design, and multifunctional module integration, thereby significantly improving the safety, effectiveness, and controllability of intracranial local drug delivery therapy.

[0074] This invention, without altering the basic clinical CED process, achieves the following through a combined design of "material selection + key dimension parameterization + structural segmentation and functionalization + system module integration": ① stable suppression of backflow within the commonly used clinical microflow rate range; ② low artifacts under MRI / CT, ​​facilitating intraoperative positioning and postoperative assessment; ③ support for rapid intraoperative trimming to match different access depths; ④ integration with navigation and image quantification modules to enhance the visualization, quantification, and controllability of the infusion process.

[0075] In a preferred embodiment, the outer sleeve 2 is made of zirconium oxide ceramic containing 3 molar percentage of yttrium oxide, but is not limited thereto.

[0076] In a preferred embodiment, the outer tube 2 has a density ≥99%, a grain size of 0.2μm to 0.6μm, a flexural strength ≥900 MPa, and a fracture toughness ≥6 MPa·m^1 / 2, but is not limited thereto.

[0077] In a preferred embodiment, the outer diameter of the outer sleeve 2 is 1.6 mm to 2.4 mm, the inner diameter is 0.80 mm to 1.10 mm, and the surface roughness of the inner wall Ra is ≤ 0.2 μm, but not limited thereto.

[0078] In a preferred embodiment, the outer wall of the distal end 21 of the outer sleeve 2 is further processed with an anti-backflow geometry, which is selected from one or more combinations of micro-step structure, concave step structure, pressure relief cavity structure and sealing ring structure, but is not limited thereto.

[0079] In a preferred embodiment, the inner sheath 1 is a medical-grade polyetheretherketone microcatheter, which is annealed at 250°C to 300°C for 1 to 2 hours after extrusion molding, and slowly cooled at a rate of 0.5°C to 1°C per hour to eliminate internal stress, but is not limited thereto.

[0080] In a preferred embodiment, the outer wall of the shearable buffer section is prefabricated with an annular graduated groove for indicating the cutting position, but this is not a limitation.

[0081] In a preferred embodiment, the connector is a locking joint, and the shearable buffer section is connected to the infusion line 3 and the scalp anchoring device 4 through the locking joint. The infusion line 3 is a rubber hose. The locking joint is provided with a sealing ring and a thrust ring. The leakage of the locking joint under a static pressure of 0.2 MPa is ≤0.01 ml / min, and the pull-out force is ≥20 N, but not limited thereto.

[0082] In a preferred embodiment, the outer diameter of the inner sleeve 1 and the inner diameter of the outer sleeve 2 are interference or transition fits, with the interference or transition amount ranging from ±5μm to ±30μm, but not limited thereto.

[0083] In a preferred embodiment, the inner sleeve 1 and the outer sleeve 2 are thermally fitted together. The inner sleeve 1 is heated to 120 degrees Celsius to 150 degrees Celsius and then inserted into the inner hole of the outer sleeve 2 at room temperature. After cooling, the inner sleeve 1 shrinks to form a tight fit with the inner wall of the outer sleeve 2, but this is not a limitation.

[0084] In a preferred embodiment, the flow rate at the catheter tip ranges from 0.5 μL / min to 3.0 μL / min, which results in a smooth radial distribution of pressure drop within the injected tissue and a quasi-spherical expansion of the drug flow front, but is not limited thereto.

[0085] The present invention also provides an intracranial drug delivery system, employing the above-described convection-enhanced drug delivery catheter assembly, and further comprising: An injection pump (not shown in the figure) is connected to infusion line 3.

[0086] The image navigation device integrated module includes a positioning adapter component 6 and a neurosurgical navigation device 7. One end of the positioning adapter component 6 holds a convection-enhanced drug delivery catheter assembly, and the other end is connected to the neurosurgical navigation device 7. At least a portion of the outer sheath 2 serves as an imaging reference area. The outer periphery or inner wall of the imaging reference area is provided with a marker pattern that can be recognized by an optical navigation system or an electromagnetic navigation system. The neurosurgical navigation device 7 drives the positioning adapter component 6 to navigate the convection-enhanced drug delivery catheter assembly based on the detected position of the imaging reference area.

[0087] In a preferred embodiment, it further includes: A magnetic resonance imaging device (not shown in the figure) generates a T1-weighted magnetic resonance image.

[0088] The drug distribution quantitative monitoring module (not shown in the figure) is based on a pre-established quantitative relationship model between the magnetic resonance T1 relaxation rate and the concentration of the contrast agent Gd-DTPA. By acquiring magnetic resonance T1-weighted images of the brain parenchyma during or after infusion, the module calculates the T1 relaxation time of each voxel and inversely calculates the Gd-DTPA concentration of the corresponding voxel, thereby generating a spatial distribution map of the drug concentration to quantitatively assess the drug distribution volume, the ratio of distribution volume to infusion volume, and backflow-related parameters. The drug distribution quantitative monitoring module is communicatively connected to the infusion pump control system to form a closed-loop control loop, enabling the infusion pump control system to dynamically adjust the infusion pump flow rate, infusion volume, or pause infusion based on the real-time monitored drug concentration distribution map, but not limited to these actions.

[0089] In a preferred embodiment, the system further includes a data processing unit (not shown in the figure), which is connected to the infusion pump, the image navigation device integration module, the magnetic resonance imaging device, and the drug distribution quantitative monitoring module. The data processing unit is configured to execute the drug distribution quantitative monitoring algorithm and visualize the operating parameters and monitoring results, but is not limited thereto.

[0090] The present invention also provides an intracranial drug delivery method, which uses the above-described intracranial drug delivery system, and cuts the shearable buffer section of the catheter assembly based on convection-enhanced drug delivery according to the access distance measured intraoperatively by the neurosurgical navigation device 7, and connects the cut shearable buffer section to the infusion line 3 through a connector.

[0091] This invention discloses a catheter assembly, an intracranial drug delivery system, and a method of use for Convection-Enhanced Delivery (CED). The catheter assembly is a coaxial composite structure of an outer cannula 2 and an inner cannula 1, which sequentially forms a catheter tip section, a rigid support section, and a shearable buffer section from distal to proximal. In the catheter tip section, the inner cannula 1 extends a length L (0.8 cm to 1.2 cm) from the distal end 21 of the outer cannula 2 and is coaxially positioned and sealed by a tapered connector 5. In the rigid support section, the outer cannula 2 covers the inner cannula 1 to provide implantation rigidity and serve as an imaging reference area. In the shearable buffer section, the inner cannula 1 extends from the proximal end 22 of the outer cannula 2 and communicates with the tip lumen, allowing for intraoperative cutting according to the access distance and rapid docking with the infusion line 3 via the connector. This invention, through the synergistic optimization of the material system (zirconia ceramic / PEEK) and parameterized structure (tip extension length, interference / heat fit, optional anti-backflow geometry, etc.), can effectively suppress backflow and reduce MRI / CT image interference, thereby improving the safety, effectiveness and controllability of intracranial local drug delivery therapy.

[0092] The following detailed description, in conjunction with the accompanying drawings, elaborates on the structure, working principle, manufacturing process, experimental verification, and specific application embodiments of the convection-enhanced drug delivery catheter assembly, intracranial drug delivery system, and their usage methods provided by the present invention. Through this detailed description, those skilled in the art can fully understand the technical solution of the present invention and its beneficial effects.

[0093] I. Detailed Structure and Component Description of the Catheter Assembly

[0094] Continue to refer to Figure 1 and Figure 2 The convection-enhanced drug delivery catheter assembly provided by this invention is based on an innovative coaxial composite structure design. The catheter assembly comprises three functional segments sequentially from its distal end (the end implanted in the brain tissue) to its proximal end (the end connected to the external device): a catheter tip segment, a rigid support segment, and a shearable buffer segment. These segments work together to achieve precise drug delivery, effective anti-backflow, and flexible intraoperative adaptation.

[0095] 1.1 Inner sleeve (1)

[0096] The inner cannula 1 is the internal channel in the catheter assembly responsible for delivering the medication. In a preferred embodiment of the invention, the inner cannula 1 is made of medical-grade polyetheretherketone (PEEK) material through a precision extrusion process. PEEK material has excellent biocompatibility (meeting USP Class VI standards), good mechanical strength, chemical stability, and excellent magnetic resonance imaging (MRI) compatibility (i.e., low artifact characteristics).

[0097] Size Specifications: The outer diameter of the inner sleeve 1 must precisely match the inner diameter of the outer sleeve 2, preferably ranging from 0.18 mm to 0.25 mm, to ensure stable delivery of the drug solution at extremely low flow rates (microliters per minute) while maintaining sufficient flow channel patency to prevent cellular or macromolecular drug aggregation and blockage. The inner wall surface is finely polished with a roughness Ra ≤ 0.2 μm to minimize flow resistance.

[0098] Processing: To eliminate internal stress generated during extrusion molding and improve dimensional stability and long-term reliability, the molded PEEK inner sleeve requires annealing. The specific process involves annealing at 250°C to 300°C in an inert gas environment for 1 to 2 hours, followed by slow cooling to room temperature at a rate of 0.5°C to 1°C per hour. This process effectively releases internal stress, preventing deformation or cracking of the conduit during subsequent assembly or use.

[0099] Functional Extension: The proximal portion of the inner cannula 1 constitutes the aforementioned shearable buffer section. Annular graduated grooves for indicating the cutting position are pre-machined on the outer wall of this section. The spacing of the grooves is, for example, 5 mm, providing a clear visual reference for the surgeon to accurately cut the catheter length as needed. The depth of the grooves has been precisely calculated and verified through finite element mechanical analysis to ensure that the catheter can be cleanly disconnected during cutting without causing internal lumen collapse or burrs, thus affecting the subsequent connection sealing.

[0100] 1.2 Outer tube (2)

[0101] The outer sheath 2 is the external support and protection structure of the conduit assembly, and it is coaxially coupled with the inner sheath 1. This invention creatively selects yttrium oxide containing 3 molar percentage (…). Partially stabilized zirconia ceramic (3Y-TZP) was used as the material for manufacturing the outer casing 2. This material choice brought several breakthrough advantages: 1. Superior mechanical properties: 3Y-TZP ceramics have extremely high flexural strength (≥900 MPa) and fracture toughness (≥6 MPa·m¹ / ²), which are far superior to conventional polymers and some metals. This provides the catheter with sufficient rigidity to support precise penetration of brain tissue and maintain post-implantation positional stability. At the same time, its toughness is sufficient to resist the impact that may be encountered during surgical operations and long-term implantation, avoiding brittle fracture.

[0102] 2. Excellent biocompatibility and stability: Zirconia ceramics are chemically extremely stable, resistant to corrosion from body fluids, and exhibit no degradation or toxic ion release even after long-term implantation, demonstrating excellent biocompatibility. Their high-temperature resistance also facilitates thorough sterilization using various methods such as high-pressure steam and ethylene oxide.

[0103] 3. Excellent medical imaging compatibility: Zirconia is a paramagnetic material that produces almost no artifacts in MRI scans (i.e., low artifacts) and moderate contrast in CT imaging. This allows the catheter containing the outer sheath 2 to not interfere with critical brain tissue images during intraoperative navigation and postoperative assessment, clearly showing the position of the catheter tip and its relationship with the surrounding target area.

[0104] 4. Smooth and low-resistance surface: The ceramic surface can achieve extremely high smoothness through precision machining.

[0105] Size specifications: The outer diameter of the outer sleeve 2 is preferably in the range of 1.6 mm to 2.4 mm (e.g., 2.0 mm) to accommodate different surgical access requirements; the inner diameter is preferably in the range of 0.80 mm to 1.10 mm (e.g., 0.90 mm) to accommodate the inner sleeve 1. Its inner wall surface roughness is also precisely polished to Ra ≤ 0.2 μm to ensure a good fit with the inner sleeve 1 and reduce the risk of medication residue in the gap.

[0106] Microstructure requirements: To achieve the above performance, the ceramic material of the outer tube 2 should have high density (≥99%) to ensure its strength and corrosion resistance; the grain size should be controlled at the nano / submicron level of 0.2 μm to 0.6 μm, which is a key microstructure feature for obtaining high strength and toughness.

[0107] Anti-backflow geometry: A specially designed anti-backflow geometry is further machined on the outer wall of the distal end 21 of the cannula 2. This structure inhibits the reverse flow (i.e., backflow) of the drug solution along the outer wall of the cannula by altering the hydrodynamic environment at the cannula-tissue interface. These geometries can be selected from one or more combinations of the following: Micro-step structure: The outer diameter decreases in a step-like manner, forming a mechanical "sealing point" within the tissue, increasing the resistance of the backflow path.

[0108] Concave step structure: Concave steps or grooves are formed in the duct wall to create local low-pressure or turbulent areas, interfering with the formation of the counterflow layer.

[0109] Pressure relief chamber structure: One or more tiny chambers are set near the tip to contain a small amount of liquid medicine that may overflow, thus buffering local pressure peaks.

[0110] Sealing ring structure: A ring-shaped protrusion surrounding the tube wall, designed to form a tighter fit with brain tissue and enhance the sealing effect.

[0111] These structures can be integrally formed with the outer tube 2 using technologies such as laser micromachining and precision grinding, ensuring a robust and reliable structure.

[0112] 1.3 Composition and Key Parameters of the Catheter Tip

[0113] The tip of the catheter is the area where the drug is actually released into the brain tissue, and its design is directly related to the infusion effect and backflow control.

[0114] In this section, the inner sleeve 1 extends a certain length L from the distal end 21 of the outer sleeve 2. This extended portion forms a flexible, slender single drug delivery port. The inner sleeve 1 is coaxially fixed and sealed to the distal end 21 of the outer sleeve 2 via a tapered connector 5. The tapered connector 5 can be made of a biomedical polymer or metal compatible with the inner sleeve 1 or the outer sleeve 2, and its tapered design facilitates assembly and ensures a secure, leak-free connection.

[0115] This invention, through extensive in vitro simulation experiments and animal studies, has found that the length L of the inner cannula 1 extending beyond the distal end 21 is a crucial parameter. When L is too short (e.g., <0.8 cm), the drug release point is too close to the end of the outer cannula. The outflow of the drug is interfered with and restricted by the geometry of the outer cannula's end, easily forming axially preferential "columnar" or "finger-like" diffusion, resulting in uneven distribution and high local shear stress. When L is too long (e.g., >1.2 cm), the slender inner cannula's support in the tissue is weakened, and the drug, after flowing out from the distal end, is more likely to flow back towards the proximal end along the low-resistance channel formed between the outer wall of the inner cannula and the tissue.

[0116] Figure 3 This is a graph showing the change in drug distribution volume over time under different catheter tip lengths, as measured in the experiment. Figure 3 The volume of drug distribution during convection-enhanced drug delivery (CED) is demonstrated under different catheter tip lengths (0.3, 0.5, 0.8, 1.0, 1.2, 1.5 cm). The trend of drug distribution over time (0–60 min) is shown in the figure. It can be seen that with the increase of the tip length (see figure caption: [insert figure here]), the drug distribution volume initially increases significantly, reaching an optimal balance at 1.0 cm. When the tip length is further extended to 1.2 cm and 1.5 cm, leakage occurs, causing the distribution volume to decrease in the later stages of injection (>30 min). The results indicate that moderately increasing the tip length helps to expand the drug distribution range, but excessive length can cause drug leakage due to tissue rupture or the formation of reflux channels, suggesting the existence of a reasonable tip length design range to achieve efficient and stable drug perfusion. Therefore, this invention optimizes the length range of L to 0.8 cm to 1.2 cm, preferably 1.0 cm. Within this range, after the drug flows out from the tip of the inner cannula 1, it can form a more ideal, near-spherical convection front in the extracellular space of brain tissue, achieving relatively balanced radial and axial diffusion. Simultaneously, this length effectively increases the fluid resistance of the backflow path, significantly reducing the backflow rate. Experimental data show that convection-enhanced drug delivery within this optimal length range can achieve the maximum and stable drug distribution volume (Vd).

[0117] 1.4 Rigid Support Section

[0118] The rigid support segment is located proximal to the catheter tip. In this segment, the inner cannula 1 is completely enclosed by the outer cannula 2. The zirconia ceramic outer cannula 2 provides the primary mechanical strength, ensuring sufficient rigidity for the catheter to penetrate the meninges and brain tissue during implantation, resisting bending, and maintaining trajectory stability after implantation, preventing catheter bending or positional deviation due to brain pulsation or tissue displacement. The low artifact characteristics of this segment also make it an ideal location reference area for intraoperative image-guided navigation systems.

[0119] 1.5 Shearable Buffer Segment and its Connection

[0120] The shearable buffer section begins at the proximal end 22 of the outer sheath 2. Here, the inner sheath 1 extends from the outer sheath 2, and its continuation forms a flexible tube segment. The inner channel of this segment is in direct communication with the lumen of the catheter tip segment.

[0121] Function: The core function of this section is to provide "trimable" flexibility. Due to individual differences in the depth of intracranial lesions and the angle of surgical approach among different patients, fixed-length catheters often cannot provide a perfect match. This invention, through the design of this shearable PEEK tube, allows the surgeon to trim off excess length on the operating table based on the actual required depth measured in real time by the neuronavigation system.

[0122] Cutting and Connection: As mentioned above, the outer wall of this section is pre-grooved with annular graduated grooves for precise cutting. Cutting can be done using sterile surgical scissors. After cutting, it needs to be reliably connected to the external infusion line 3 via a connector. This connector is preferably a locking fitting (e.g., a Luer lock fitting or a custom compression fitting). The locking fitting integrates a sealing ring (e.g., an O-ring) and a thrust ring to ensure sealing and pull-out resistance after connection. In one embodiment, the locking fitting is required to have a leakage rate ≤0.01 ml / min and a pull-out force ≥20 N under a static pressure of 0.2 MPa to meet clinical safety standards.

[0123] Infusion tubing and anchoring: The infusion tubing 3 is typically a soft, medical-grade silicone or rubber tubing that connects to the infusion pump. The catheter assembly can also be secured to the patient's skull or scalp via connectors or a separate scalp anchoring device 4 to prevent accidental displacement or dislodgement of the catheter postoperatively.

[0124] 1.6 Fitting process of inner sleeve and outer sleeve

[0125] The fit quality between the inner sheath 1 and the outer sheath 2 directly affects the overall sealing and mechanical integrity of the catheter. This invention preferably employs an interference fit or a transition fit, with an interference or transition amount ranging from ±5μm to ±30μm. To achieve this precise fit and avoid the use of adhesives that may pose biocompatibility risks, this invention employs a heat-fitting process: 1. Heat the PEEK inner sleeve 1 to a specific temperature range above its glass transition temperature and below its melting point, for example, 120 to 150 degrees Celsius. At this temperature, the PEEK material softens and expands.

[0126] 2. Keep the zirconia ceramic outer tube 2, which is at room temperature (approximately 25 degrees Celsius), in place.

[0127] 3. Quickly insert the heated and expanded inner sleeve 1 into the inner hole of the outer sleeve 2.

[0128] 4. Natural cooling or controlled cooling. During the cooling process, the PEEK inner sleeve 1 contracts. Because its coefficient of thermal expansion is greater than that of zirconia ceramic, significant shrinkage stress will be generated at the interface after cooling, thus forming a strong and tight adhesive-free mechanical lock with the inner wall of the ceramic.

[0129] 5. Before assembly, plasma cleaning can be performed on the outer surface of the PEEK inner sleeve 1 and the inner surface of the zirconium oxide outer sleeve 2 to remove organic contaminants, activate the surface, and further improve the interface bonding quality and long-term stability.

[0130] II. Composition and Integration of Intracranial Drug Delivery Systems

[0131] Figure 4 This is a schematic diagram illustrating the integration of the catheter and neurosurgical navigation device of the present invention. Figure 4 As shown, the catheter assembly of the present invention is the core of the intracranial drug delivery system, which integrates a variety of modern medical devices to achieve precise, visual, and controllable convection-enhanced drug delivery throughout the entire process.

[0132] 2.1 Injection Pump

[0133] An infusion pump is a power source that provides continuous, stable pressure to drive the flow of medication. Connected to the infusion line 3 of the catheter assembly, it allows for precise setting and adjustment of the infusion rate (e.g., within the range of 0.5 μL / min to 3.0 μL / min), infusion volume, and infusion time. The infusion pump should possess high precision, low pulsation, programmability, and the ability to communicate with external control systems.

[0134] 2.2 Image Navigation Device Integration Module

[0135] This module is designed to enable real-time, high-precision navigation during catheter implantation.

[0136] Neurosurgical navigation device 7: This can be a commercial neurosurgical navigation system based on optical or electromagnetic tracking, such as Brainlab, StealthStation, etc.

[0137] Positioning adapter component 6: This is a mechanical connection device, one end of which is designed with a special clamping mechanism for firmly clamping the rigid support section of the outer sheath 2 of the catheter assembly of the present invention; the other end is connected to the positioning arm or reference frame of the neurosurgical navigation device 7.

[0138] Imaging reference area and markers: At least a portion of the outer tube 2 (typically a rigid support section) is designed as an imaging reference area. An array of reflective spheres that can be recognized by the camera of an optical navigation system, or a miniature electromagnetic induction coil (not shown in the figure, integrated within the structure) that can be detected by an electromagnetic navigation system, is disposed on the outer periphery or inner wall of this area. These markers have a known and fixed geometric relationship with the tip of the conduit.

[0139] Workflow: Preoperatively, the patient's MRI or CT image data is imported into the navigation system and registered. During the procedure, the navigation system 7 monitors the spatial position of the positioning adapter 6 and markers installed on the catheter in real time, thereby displaying the virtual catheter trajectory and tip position on the preoperative images in real time and dynamically. Based on this, the physician can plan the optimal puncture path and, under navigation guidance, precisely implant the catheter into the pre-set target point, greatly improving the accuracy and safety of implantation.

[0140] 2.3 Drug Distribution Quantitative Monitoring Module (Integrated with Magnetic Resonance Imaging Equipment)

[0141] This is the key innovative module of the system of this invention that realizes "process visualization" and "closed-loop control". It solves the pain point of "blind operation" in traditional CED.

[0142] Magnetic resonance imaging (MRI) equipment: used to perform rapid MRI scans of the patient's head during or after infusion, particularly to acquire T1-weighted images. Fast imaging sequences can be used to reduce motion artifacts.

[0143] Quantitative monitoring principle: Many drugs or their co-infused tracers (such as the commonly used magnetic resonance contrast agent gadopentetate dimeglumine, Gd-DTPA) alter the magnetic resonance relaxation characteristics of local tissues, particularly shortening the T1 relaxation time, which manifests as signal enhancement (brightness) on T1-weighted images. This invention establishes a quantitative relationship model between Gd-DTPA concentration (C) and its induced change in T1 relaxation rate (ΔR1, R1 = 1 / T1) through in vitro or in vivo experiments. This relationship typically exhibits good linearity within a certain concentration range: ΔR1 = r1 C, where r1 is the relaxation rate constant of Gd-DTPA.

[0144] Monitoring process: Obtaining T1 map: During the infusion process, multiple sets of images with different inversion times or flip angles are rapidly acquired using MRI equipment. These image data are then used to reconstruct the T1 relaxation time map of the entire brain scan area.

[0145] Concentration distribution calculation: The obtained T1 map is compared with the baseline T1 map before infusion, and ΔR1 is calculated for each voxel (3D pixel). Then, using a pre-established ΔR1-C quantitative relationship model, the Gd-DTPA concentration corresponding to each voxel is retrieved, thereby generating a "spatial distribution map of drug concentration". Different colors or brightness in the map represent different drug concentrations.

[0146] Quantitative assessment parameters: Based on this concentration distribution map, a series of key assessment parameters can be calculated automatically or semi-automatically. Drug distribution volume (Vd): The total volume of voxels exceeding a certain threshold concentration (e.g., 3 times the background noise).

[0147] Distribution volume to infusion volume ratio (Vd / Vi): This reflects infusion efficiency; a higher ratio indicates better drug retention and distribution in tissues.

[0148] Countercurrent-related parameters: such as the length of the high-concentration region along the duct wall (countercurrent length), countercurrent volume, etc.

[0149] Closed-loop control system: The drug distribution and quantification monitoring module communicates with the infusion pump control system via a data interface, forming a closed-loop control system. When real-time monitoring detects that the drug distribution does not cover the target area, significant backflow occurs, or the concentration distribution is unsatisfactory, the monitoring module can send instructions to the infusion pump control system to dynamically adjust the infusion pump flow rate (e.g., reduce it to slow backflow), pause the infusion, or adjust the subsequent infusion volume, thereby achieving personalized and adaptive drug delivery based on real-time feedback.

[0150] 2.4 Data Processing Unit

[0151] The data processing unit is the "brain" of the system, typically a high-performance workstation or embedded computer. It connects to the infusion pump, image navigation integrated module, magnetic resonance imaging equipment, and drug distribution and quantification monitoring module.

[0152] Function: 1. Receive and fuse data from various modules (such as navigation coordinates, pump flow rate, MRI images).

[0153] 2. Run the drug distribution quantitative monitoring algorithm to perform T1 plot reconstruction and concentration inversion calculation.

[0154] 3. Provides a graphical user interface to visualize key operating parameters (current flow rate, infused volume, catheter tip navigation position), real-time drug concentration distribution maps, and calculated evaluation results such as Vd and Vd / Vi, providing doctors with intuitive decision support.

[0155] 4. Store data from the entire treatment process for postoperative analysis and case review.

[0156] III. Manufacturing Process Route of Conduit Assembly

[0157] To ensure the consistency and reliability of the conduit assembly performance, a strict manufacturing process must be followed.

[0158] 3.1 Manufacturing of the zirconia ceramic outer sleeve (2)

[0159] 1. Raw material preparation and pulping: High-purity 3Y-TZP nanoparticles (Zr) are used. + 3 mol% Mix the slurry with deionized water, dispersant (such as ammonium polyacrylate), binder and plasticizer in a certain proportion, and ball mill for more than 48 hours to form a uniform, stable ceramic slurry with a high solid content (50-60%).

[0160] 2. Forming: Ceramic Injection Molding (CIM) technology is used. The slurry is injected into a precisely designed mold to form a "hollow rod"-shaped green body with a preset inner hole, outer diameter, and anti-backflow geometry at the far end.

[0161] 3. Degreasing and pre-firing: In air or a protective atmosphere, the organic binders and plasticizers in the green body are completely decomposed and volatilized (degreasing) using a programmed temperature increase (e.g., slowly increasing to 600-900°C). Subsequently, pre-firing is carried out at a higher temperature (e.g., 1200-1300°C) to allow the ceramic particles to initially bond together, obtaining a green body with a certain strength.

[0162] 4. Sintering: Final sintering is carried out in a high-temperature sintering furnace (such as in a vacuum atmosphere or air atmosphere) at 1500-1600°C for 2-4 hours. During this process, the ceramic particles become denser, and the volume undergoes linear shrinkage (shrinkage rate of approximately 15-20%). This shrinkage rate has been precisely compensated for in the mold design to ensure that the final product dimensions meet the design requirements. The density of the material after sintering must reach above 99%.

[0163] 5. Finishing: Diamond grinding tools are used to grind the inner hole to achieve the designed inner diameter size (0.80-1.10 mm) and extremely high roundness and cylindricity.

[0164] Using ultra-precision grinding machines or femtosecond laser micromachining systems, the anti-backflow geometry (microsteps, grooves, etc.) of the outer wall is finally shaped and finished.

[0165] The inner wall is mechanically-chemically polished or ultrasonically ground to ensure a surface roughness Ra ≤ 0.2 μm.

[0166] 6. Cleaning and Inspection: Ultrasonic cleaning removes processing residues, followed by comprehensive inspection of dimensional accuracy, appearance defects, microstructure (metallographic examination of grain size) and mechanical properties (sampling for three-point bending strength testing).

[0167] 3.2 Manufacturing of PEEK inner sleeve (1)

[0168] 1. Precision Extrusion: Medical-grade PEEK granules are melted in an extruder and continuously extruded into pipes through an extrusion die with a precision core and sleeve. An online laser diameter gauge is used for real-time monitoring to ensure that the outer diameter tolerance is controlled within ±10 μm.

[0169] 2. Fixed-length cutting and end treatment: Cut to the required length and chamfer or polish the ends to prevent burrs.

[0170] 3. Annealing treatment: Place the cut PEEK tubes in a programmable temperature controlled furnace and heat them to 250-300°C under nitrogen protection. Hold the temperature for 1-2 hours to eliminate internal stress. Then cool them to room temperature at a very slow rate (0.5-1°C / minute).

[0171] 4. Inner wall polishing: If necessary, a micro polishing tool connected to a flexible shaft can be used to lightly polish the inner wall of the tube to ensure the smoothness of the inner wall.

[0172] 5. Scale groove machining: Annular scale grooves are machined on the outer wall of the shearable buffer section using laser engraving or precision machining.

[0173] 3.3 Component Assembly and Testing

[0174] 1. Surface treatment: The outer surface of the PEEK inner sleeve 1 and the inner surface of the zirconia outer sleeve 2 are activated by plasma cleaning.

[0175] 2. Heated Fitting: Place the PEEK inner sleeve 1 in a precision temperature control device and heat it to 120-150°C, maintaining a stable temperature. Quickly insert the heated inner sleeve into the inner hole of the outer sleeve 2 at room temperature until the tip of the inner sleeve extends beyond the far end of the outer sleeve to the preset length L (0.8-1.2 cm). Use a limiting fixture to ensure accurate length. Allow to cool naturally to room temperature.

[0176] 3. Install the tapered connector (5): At the tip of the catheter, put the tapered connector 5 on the inner sleeve 1 and fix it to the distal end of the outer sleeve 2 with medical adhesive (such as medical epoxy resin) or mechanical means (such as heat fusion) to ensure coaxiality and sealing.

[0177] 4. Install the proximal connector: Install the female part of the locking connector at the end of the shearable buffer section.

[0178] 5. Comprehensive testing: Dimension and appearance inspection: Confirm the overall length, length of each section, coaxiality, etc.

[0179] Air tightness test: Introduce clean compressed air or nitrogen at 200 kPa into the conduit, maintain the pressure for 30 seconds, and the pressure drop should be within the allowable range (i.e., no visible air bubbles).

[0180] Flow resistance test: Connect a precision syringe pump and a pressure sensor, and infuse physiological saline at different flow rates of 0.5, 1.0, and 2.0 µL / min, recording the pressure difference between the inlet and outlet. The flow resistance curve should have good linearity (R² ≥ 0.99) and the values ​​should be within the preset range, indicating that the lumen is patent and there is no local blockage.

[0181] Connection strength test: Perform a pull-out force test on the locking joint to ensure ≥20 N.

[0182] 3.4 Sterilization and Packaging

[0183] Qualified products that pass the testing are sterilized using ethylene oxide (EtO) or gamma rays. After sterilization, critical dimensions and interfacial bonding strength are re-inspected to ensure that the sterilization process has not caused material performance degradation or significant dimensional changes (e.g., critical dimension drift < ±0.02 mm, interfacial strength retention > 95%). Finally, the products are packaged using a double-layer aseptic barrier system (e.g., inner Tyvek bag, outer plastic pallet), and product information and sterilization expiration date are labeled.

[0184] IV. Specific Application Examples and Experimental Verification

[0185] The superior performance of the catheter assembly and system of the present invention will be further illustrated in detail below through several specific experimental embodiments.

[0186] Example 1: In vitro simulation verification of the effect of catheter tip length L on drug distribution

[0187] Objective: To verify the key role of the inner cannula 1 extension length L in the range of 0.8-1.2 cm in achieving ideal drug distribution and inhibiting backflow.

[0188] Materials and Methods: 1. Prepare three sets of catheter samples, varying only the L value: Group A (L=0.5 cm), Group B (L=1.0 cm), and Group C (L=1.5 cm). The inner diameter of the inner cannula is 0.20 mm, and the outer diameter of the outer cannula is 2.0 mm.

[0189] 2. A cylindrical block was made using 0.6% agarose gel to simulate brain tissue (with an elastic modulus close to that of brain parenchyma).

[0190] 3. Insert the catheter vertically into the gel at a fixed depth.

[0191] 4. Connect the syringe pump and inject the buffer containing blue dye at a constant flow rate of 2.0 µL / min for 60 minutes.

[0192] 5. Use a high-definition camera to periodically photograph the diffusion of the dye in the gel. After the experiment, cut the gel along the axis of the conduit and observe the cross-sectional distribution.

[0193] 6. Measured using image analysis software: distribution volume (Vd, estimated by image thresholding and 3D reconstruction), maximum radial diffusion radius (R_rad), maximum axial diffusion length (L_axial), reflux length along the duct wall (RefluxLength), and aspect ratio of the (axial / radial) distribution pattern (AR = L_axial / (2×R_rad)).

[0194] 7. Results (see Figure 3 ): Group A (L=0.5 cm): Drug diffusion exhibited a distinct "columnar" pattern, with an AR value significantly greater than 1. Axial diffusion was extensive, but radial diffusion was limited, resulting in a moderate distribution volume. Backflow was minimal because the release point was close to the outer sheath, allowing the outflowing drug to rapidly penetrate deep into the tissue.

[0195] Group B (L=1.0 cm): The drug diffusion morphology was closest to "spherical" or "quasi-spherical", with an AR value close to 1. Radial and axial diffusion were balanced, achieving the maximum distribution volume (Vd) at 60 minutes. The countercurrent length was extremely short or almost unobservable, indicating that the hydrodynamics reached optimal equilibrium at this length.

[0196] Group C (L=1.5 cm): Initially, large diffusion clusters formed, but as time progressed, a distinct dye "tail" was clearly observed extending proximally along the duct wall, indicating significant backflow. The backflow length was the longest. Due to the large amount of drug loss into the backflow channel, the effective forward distribution volume (Vd) decreased in the later stages.

[0197] Conclusion: In vitro simulation experiments confirmed that L = 1.0 cm (within the range of 0.8-1.2 cm required by this invention) is the optimal parameter for achieving low backflow, large volume, and spherical uniform distribution. Too short a length leads to poor distribution morphology, while too long a length causes severe backflow. This provides direct experimental basis for the structural parameter design of the catheter.

[0198] Example 2: Validation of MRI-based quantitative monitoring of Gd-DTPA concentration distribution

[0199] Objective: To demonstrate the workflow and accuracy of the drug distribution quantitative monitoring module in the system of this invention.

[0200] Materials and Methods: 1. Establish a quantitative model: Prepare a series of Gd-DTPA aqueous solutions with known concentrations (e.g., 0, 0.5, 1.0, 2.0, 4.0 mM). Using a clinical 3T MRI scanner, employ a multi-flip angle fast small-angle excitation (FLASH) sequence to acquire T1-weighted image sets for each sample. Calculate the T1 relaxation time for each sample by fitting the data, and calculate the relaxation rate R1 (=1 / T1). Plot the Gd-DTPA concentration on the x-axis and ΔR1 (sample R1 minus pure water R1) on the y-axis, and perform linear fitting to obtain the relaxation rate constant r1 (unit: m). ¹ ¹).

[0201] 2. In vivo verification: The catheter of this invention (L=1.0 cm) was stereotactically implanted into the brain of a rat. An infusion pump was then connected.

[0202] 3. Infusion and Imaging: A simulated drug solution containing 2.0 mM Gd-DTPA was infused at a flow rate of 1.0 µL / min, with a total volume of 10 µL. MRI scans were performed before the start of the infusion (baseline), during the infusion (e.g., after 5 µL infusion), and immediately after the infusion was completed to obtain T1 images.

[0203] 4. Data Processing: Register the T1 map during / after infusion with the baseline T1 map. Calculate ΔR1 for each voxel. Using the model established in step 1 (C = ΔR1 / r1), calculate the Gd-DTPA concentration for each voxel and generate a two-dimensional or three-dimensional concentration distribution map. Figure 5 This is a schematic diagram illustrating the principle and mathematical model of calculating Gd-DTPA concentration distribution based on magnetic resonance T1 relaxation rate inversion in this invention. (Reference) Figure 5 As shown, previous studies have established a formula for calculating the relationship between the T1 relaxation rate and concentration of Gd-DTPA in in vitro tissue suspensions, and based on this, the concentration distribution of the drug in the rat cranium has been determined.

[0204] 5. Results Analysis: The generated concentration distribution map clearly shows the high-concentration core area, the diffusion front, and whether there are abnormally high-concentration bands along the duct (indicating backflow). The system automatically calculates parameters such as Vd and Vd / Vi. The drug diffuses outward from the duct tip in an approximately spherical shape, consistent with the in vitro results of Example 1. The calculated Vd / Vi ratio reflects the retention and diffusion efficiency of the drug in brain tissue. This experiment demonstrates that real-time, quantitative, and visual monitoring of convection-enhanced drug delivery can be achieved using conventional clinical MRI equipment and the quantitative algorithm of this invention.

[0205] Example 3: Evaluation of the efficacy of CED catheter-delivered tumor-infiltrating lymphocytes (TILs) in the treatment of glioma

[0206] Objective: To verify the advantages of the catheter of the present invention in enhancing convection for delivering large-sized bioactive cells (such as immune cells).

[0207] Materials and Methods: 1. Animal model: Establish a rat orthotopic glioma model (such as C6 or 9L glioma cell lines).

[0208] 2. Grouping and Treatment: After the tumors grew to a certain size, they were randomly divided into three groups: Sham surgery group: Only craniotomy and brain puncture were performed, without catheter implantation or cell infusion.

[0209] Traditional local drug delivery group (Control): A conventional intracranial drug delivery catheter (such as a fixed-length polymer cannula) was implanted, and a TILs cell suspension was locally injected at the tumor center at a flow rate of 22 µL / min.

[0210] CED administration group (CED): The catheter assembly of the present invention (L=1.0 cm) was implanted, and convection-enhanced drug delivery was performed at the same flow rate and cell dose.

[0211] 3. Sampling and Analysis: The animal was euthanized 24 hours after infusion and the brain was harvested. Coronal sections of brain tissue were taken from the injection point (0 mm), 2 mm distal, and 4 mm distal, with the catheter tip as the origin.

[0212] 4. Immunohistochemical staining: CD3 immunohistochemical staining (labeling T lymphocytes) was performed on the sections. The infiltration density and distribution range of CD3-positive T cells in three different planes were observed and compared under a microscope.

[0213] 5. Results: Figure 6 This image shows a comparison of staining results between the convection-enhanced drug delivery catheter assembly of this invention and other subcutaneous injection tools in a rat orthotopic glioma model. (Reference) Figure 6As shown, the spatial distribution map of Gd-DTPA concentration in the rat brain was successfully obtained. Among them, at the injection point plane (0 mm): significant T cell infiltration was observed in both the Control group and the CED group, which was significantly more than that in the Sham group.

[0214] At the distal 2 mm and 4 mm planes: a large number of CD3-positive T cells were still diffusely infiltrated in and around the tumor tissue in the CED group, indicating that the cells were transported by convection to areas far from the injection site. In contrast, the T cell signal in the Control group decreased sharply at the distal plane, confined to a very small area near the injection site.

[0215] Conclusion: The CED catheter of this invention can effectively deliver and widely distribute large-sized therapeutic cells such as TILs to the target tumor area, significantly expanding the scope of cell therapy. In contrast, traditional local injection methods rely mainly on cell diffusion, resulting in extremely limited distribution. This highlights the unique advantages of CED technology in handling "biological agents" such as macromolecules, nanoparticles, and cells, and the effectiveness of the catheter of this invention in this application.

[0216] Example 4: Preliminary Study on the Immunomodulatory Effect of CED Physical Pressure on the Tumor Microenvironment

[0217] Objective: To explore the potential impact of the CED infusion process itself (even just the infusion of buffer solution) on the tumor immune microenvironment.

[0218] Materials and Methods: 1. Animal Model and Grouping: A mouse GL261 orthotopic glioma model was established as in Example 3. The mice were randomly divided into three groups: Untreated control group (NC) Control group: Phosphate-buffered saline (PBS) was administered locally using a conventional catheter.

[0219] CED-infused PBS group (CED): An equal volume of PBS is infused using the catheter of the present invention in a CED manner.

[0220] 2. Treatment plan: After the tumor is established, administer an infusion once a day for 3 consecutive days.

[0221] 3. Sampling and analysis: Brain tissue was harvested the day after the last infusion, and paraffin sections containing the largest cross-section of the tumor were prepared for CD3 immunohistochemical staining.

[0222] 4. Results: Figure 7 Immunohistochemical staining comparison and magnified view of the effect of CED infusion of PBS via the convection-enhanced drug delivery catheter assembly of the present invention on the promotion of CD3-positive T cell infiltration in the tumor microenvironment, compared with the conventional local drug delivery and untreated groups. Figure 7As shown, compared with the NC and Control groups, the CED-PBS group exhibited a significantly increased density of CD3-positive T cells infiltrating the tumor tissue. High-power microscopy revealed that the T cells were not only more numerous but also infiltrated deeper into the tumor parenchyma.

[0223] 5. Conclusion: This interesting finding suggests that the convective forces and interstitial fluid pressure changes generated by CED may themselves promote the recruitment and infiltration of immune cells into the tumor region, thereby altering the immunosuppressive tumor microenvironment to some extent and transforming it into a "hot tumor." This provides new theoretical basis and potential for synergistic effects in the combined application of CED technology and immunotherapy (such as immune checkpoint inhibitors).

[0224] Example 5: Evaluation of the enhanced efficacy of local CED delivery of PD-1 antibody in the treatment of glioma

[0225] Objective: Based on the findings of Example 4, to verify whether local delivery of immune checkpoint inhibitors (anti-PD-1 antibodies) to the CED using the catheter of the present invention can enhance the anti-tumor efficacy.

[0226] Materials and Methods: 1. Animal model: Establish a mouse GL261-luc orthotopic glioma model (tumor cells express luciferase, which facilitates in vivo imaging monitoring).

[0227] 2. Grouping and Treatment (See the experimental flowchart for details) Figure 8 (part a) Untreated group (NC) Systemic group: Anti-PD-1 antibody (equivalent dose) was administered via tail vein injection.

[0228] CED local administration group (CED): The catheter of the present invention is implanted, and the same dose of anti-PD-1 antibody is directly infused into the tumor area through CED.

[0229] 3. Treatment and Monitoring: Treatment began on day 10 post-tumor inoculation (after confirmation of tumor formation) and continued for 4 days (days 10-13). Tumor burden (fluorescence signal intensity) was monitored using a bioluminescence imaging (BLI) system on day 10 (before treatment) and day 20 (after treatment). At the experimental endpoint, brain tissue was harvested for H&E staining to observe tumor necrosis and morphological changes.

[0230] 4. Results (see Figure 8 (Parts b and c) Figure 8 This is a graph evaluating the efficacy of CED local delivery of PD-1 antibody for the treatment of mouse GL261 glioma using the convection-enhanced drug delivery catheter assembly of the present invention. Figure 8As shown in the BLI imaging, on day 20, the tumor bioluminescence signal intensity in the CED local administration group was significantly lower than that in the systemic administration group and the untreated group, indicating that local delivery of anti-PD-1 antibody by CED can more effectively inhibit tumor growth.

[0231] Pathology: H&E staining showed that the CED treatment group had a larger area of ​​necrosis in the tumor tissue and more disordered tumor cell structure, further confirming its stronger anti-tumor effect.

[0232] Conclusion: Local delivery of immune checkpoint inhibitors using the CED catheter of this invention can significantly improve the concentration and distribution of the drug at the tumor site, and may synergize with the immune microenvironment regulation effect of the CED itself, thereby producing anti-tumor efficacy superior to traditional systemic administration. This demonstrates the great application potential of this invention in the field of precision immunotherapy.

[0233] V. Specific Steps for Intracranial Drug Delivery

[0234] Combining the above-described catheter assembly and system, the intracranial drug delivery method of the present invention includes the following steps: 1. Preoperative planning: Obtain high-resolution preoperative MRI or CT images of the patient.

[0235] On the imaging workstation, the optimal catheter implantation target point and puncture path are planned based on the location, size, and surrounding functional areas of the lesion. The theoretically required catheter implantation depth is determined.

[0236] 2. System preparation and registration: Import preoperative imaging data into the neurosurgical navigation device 7.

[0237] Connect and calibrate all devices: infusion pump, navigation system, MRI equipment (e.g., for intraoperative monitoring), and data processing unit.

[0238] Register the patient's head with a navigation system (e.g., by scanning after attaching a reference marker, or by registering using a mask).

[0239] 3. Catheter preparation and cutting: Open the packaging of the catheter assembly of the present invention under aseptic conditions.

[0240] The final working length of the catheter is determined based on the actual puncture path length (distance from the skull inlet to the target point) measured and confirmed in real time during the procedure by the navigation system.

[0241] Observe the annular graduations on the shearable buffer section of the catheter. At a graduation slightly longer than the required length, use sterile surgical scissors to make a precise cut. After cutting, check if the cut is smooth.

[0242] The proximal end of the cut catheter is reliably connected to the infusion line 3 via a locking connector, and a simple flushing and air venting is performed.

[0243] 4. Navigation-guided catheter implantation: The catheter positioning adapter 6 is mounted on the robotic arm of the neurosurgical navigation device 7. The navigation system identifies markers on the catheter.

[0244] Following the pre-planned path, the skull drilling and dural incision were performed under real-time navigation guidance.

[0245] With the aid of navigation visualization, the catheter assembly is slowly and smoothly advanced along the planned path until the virtual catheter tip precisely coincides with the pre-set target point on the navigation screen.

[0246] Fixing the catheter: Use the scalp anchoring device 4 to securely fix the outer tube portion of the catheter to the skull or scalp to prevent displacement.

[0247] 5. Infusion and Real-time Monitoring (Optional / Advanced Applications): Connect infusion line 3 to the syringe pump that is already loaded with the medication.

[0248] Begin infusion. The initial flow rate is typically set in a low range (e.g., 0.5-1.0 µL / min), and adjusted as needed.

[0249] If an intraoperative MRI and quantitative monitoring module is integrated, rapid MRI scans can be performed during infusion. The data processing unit generates drug concentration distribution maps in real time and calculates parameters such as Vd and reflux.

[0250] Based on real-time monitoring results, doctors can determine whether to continue infusion if the distribution is ideal, or if significant backflow or failure to cover the target area occurs. In such cases, the parameters of the infusion pump can be dynamically adjusted (e.g., pause, reduce flow rate, or change infusion strategy).

[0251] 6. End of infusion and postoperative management: After the preset infusion volume is completed, stop the infusion pump.

[0252] A second MRI scan can be performed to obtain the final drug distribution results for evaluation.

[0253] Depending on the treatment plan, the catheter can be left in place for subsequent fractionated infusions (in which case strict management is required to prevent infection), or the catheter can be carefully removed and the wound closed.

[0254] Postoperatively, patients should undergo necessary neurological function observation and imaging follow-up.

[0255] VI. Summary of the Beneficial Effects of the Invention

[0256] In summary, the convection-enhanced drug delivery catheter assembly, drug delivery system, and method provided by this invention systematically address the core challenges currently facing the clinical translation of CED technology through multiple innovations at the levels of materials, structure, function, and system integration. 1. Significantly enhanced backflow control: By optimizing the extension length of the inner cannula tip (0.8-1.2 cm) and combining it with the anti-backflow geometry of the outer cannula distal end, the backflow of the drug solution along the cannula wall is effectively suppressed from the source of fluid dynamics, expanding the safe infusion flow rate window and ensuring efficient forward distribution of the drug solution.

[0257] 2. Excellent compatibility with medical imaging: The composite material of zirconia ceramic and PEEK provides sufficient mechanical strength while achieving low artifact characteristics under important imaging equipment such as MRI. This makes it possible to accurately implant the catheter, locate it in real time and evaluate it after surgery, without affecting the observation of brain tissue and drug distribution.

[0258] 3. High flexibility and adaptability during surgery: The innovative shearable buffer section design allows the surgeon to cut the length on-site according to the patient's individual anatomy, realizing "one tube for multiple uses" and avoiding repeated punctures, instrument changes, or compromises in the approach due to mismatched catheter lengths, thus improving surgical efficiency and safety.

[0259] 4. Visualization and Controllability of Infusion Process: Integrating an MRI-based quantitative drug distribution monitoring module transforms the CED from a "blind operation" into a "visualized and quantifiable" precision process. Real-time feedback forms a closed-loop control, dynamically optimizing infusion parameters to maximize therapeutic benefits and minimize side effect risks.

[0260] 5. Expanded Treatment Scope and Efficacy: Experiments have demonstrated that this catheter system is not only suitable for small molecule drugs, but also for the efficient delivery of large-sized therapeutic agents such as antibodies, nanoparticles, and even live cells. It may also possess the potential to modulate the tumor immune microenvironment, opening new avenues for combined application with cutting-edge treatments such as immunotherapy.

[0261] Therefore, this invention represents a significant advancement in intracranial local drug delivery technology, and is expected to significantly improve the safety, efficacy, and controllability of local treatment for various intracranial diseases such as malignant brain tumors, neurodegenerative diseases, and genetic diseases of the central nervous system. It has broad clinical application prospects and significant social value.

[0262] In summary, the purpose of this invention is to provide a convection-enhanced drug delivery system, a drug delivery system, and a method of use. Through innovative material combinations, precise parametric structural design, and multifunctional module integration, it systematically solves the bottleneck problems faced by traditional CED technology, such as difficulty in backflow control, large image interference, poor intraoperative flexibility, and lack of process visualization, thereby significantly improving the safety, effectiveness, and controllability of intracranial local drug delivery therapy.

[0263] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A catheter assembly based on convection-enhanced drug delivery, characterized in that, include: The catheter assembly consists of an outer sheath (2) and an inner sheath (1) arranged coaxially. The catheter assembly includes a catheter tip section, a rigid support section, and a shearable buffer section from the distal end to the proximal end. In the catheter tip section, the inner sheath (1) extends from the distal end (21) of the outer sheath (2) and is coaxially fixed with the outer sheath (2) by a tapered connector (5). The length of the inner sheath (1) extending from the distal end (21) is L, and the length of L ranges from 0.8 cm to 1.2 cm. In the rigid support section, the outer sleeve (2) covers the inner sleeve (1). In the shearable buffer section, the inner sheath (1) extends from the proximal end (22) of the outer sheath (2), the inner channel of the shearable buffer section communicates with the inner lumen of the catheter tip section, and the shearable buffer section is configured to connect to the infusion line (3) via a connector after being sheared.

2. The catheter assembly based on convection-enhanced drug delivery according to claim 1, characterized in that, The outer tube (2) is made of zirconium oxide ceramic containing 3 molar percentage of yttrium oxide.

3. The convection-enhanced drug delivery assembly according to claim 2, characterized in that, The outer tube (2) has a density of ≥99%, a grain size of 0.2μm to 0.6μm, a bending strength of ≥900 MPa, and a fracture toughness of ≥6 MPa·m^1 / 2.

4. The catheter assembly based on convection-enhanced drug delivery according to claim 2, characterized in that, The outer diameter of the outer sleeve (2) is 1.6 mm to 2.4 mm, the inner diameter is 0.80 mm to 1.10 mm, and the surface roughness of the inner wall is Ra≤0.2 μm.

5. The catheter assembly based on convection-enhanced drug delivery according to claim 1, characterized in that, The outer wall of the distal end (21) of the outer sleeve (2) is also processed with an anti-backflow geometry, which is selected from one or more combinations of micro-step structure, concave step structure, pressure reducing cavity structure and sealing ring structure.

6. The catheter assembly for convection-enhanced drug delivery according to claim 1, characterized in that, The inner sheath (1) is a medical-grade polyether ether ketone microcatheter, which is annealed at 250°C to 300°C for 1 to 2 hours after extrusion molding, and slowly cooled at a rate of 0.5°C to 1°C per hour to eliminate internal stress.

7. The convection-enhanced drug delivery assembly according to claim 6, characterized in that, The outer wall of the shearable buffer section is prefabricated with annular graduated grooves for indicating the cutting position.

8. The catheter assembly based on convection-enhanced drug delivery according to claim 1, characterized in that, The connector is a locking joint. The shearable buffer section is connected to the infusion line (3) and the scalp anchoring device (4) through the locking joint. The infusion line (3) is a rubber hose. The locking joint is equipped with a sealing ring and a thrust ring. The leakage of the locking joint under a static pressure of 0.2 MPa is ≤0.01 ml / min, and the pull-out force is ≥20 N.

9. The convection-enhanced drug delivery assembly according to claim 1, characterized in that, The outer diameter of the inner sleeve (1) and the inner diameter of the outer sleeve (2) are in an interference or transition fit, with the interference or transition amount being positive 5μm to positive 30μm.

10. The convection-enhanced drug delivery assembly according to claim 9, characterized in that, The inner sleeve (1) is thermally fitted with the outer sleeve (2). The inner sleeve (1) is heated to 120 degrees Celsius to 150 degrees Celsius and then inserted into the inner hole of the outer sleeve (2) at room temperature. After cooling, the inner sleeve (1) shrinks and forms a tight fit with the inner wall of the outer sleeve (2).

11. The convection-enhanced drug delivery assembly according to claim 1, characterized in that, The flow rate at the tip of the catheter ranges from 0.5 μL / min to 3.0 μL / min, which allows the pressure drop within the injected tissue to be smoothly distributed radially and the drug flow front to expand in a quasi-spherical shape.

12. An intracranial drug delivery system, characterized in that, The catheter assembly based on convection-enhanced drug delivery as described in claim 1 further includes: An injection pump is connected to the infusion line (3); The image navigation device integrated module includes a positioning adapter component (6) and a neurosurgical navigation device (7). One end of the positioning adapter component (6) holds the convection-enhanced drug delivery catheter assembly, and the other end is connected to the neurosurgical navigation device (7). At least a portion of the outer sheath (2) serves as an imaging reference area. The outer periphery or inner wall of the imaging reference area is provided with a marker pattern that can be recognized by an optical navigation system or an electromagnetic navigation system. The neurosurgical navigation device (7) drives the positioning adapter component (6) to navigate the convection-enhanced drug delivery catheter assembly based on detecting the position of the imaging reference area.

13. The intracranial drug delivery system according to claim 12, characterized in that, Also includes: Magnetic resonance imaging equipment generates T1-weighted magnetic resonance images; The drug distribution quantitative monitoring module is based on a pre-established quantitative relationship model between magnetic resonance T1 relaxation rate and contrast agent Gd-DTPA concentration. By acquiring magnetic resonance T1-weighted images of brain parenchyma during or after infusion, the module calculates the T1 relaxation time of each voxel and inversely calculates the Gd-DTPA concentration of the corresponding voxel, thereby generating a spatial distribution map of drug concentration to quantitatively assess drug distribution volume, the ratio of distribution volume to infusion volume, and backflow-related parameters. The drug distribution quantitative monitoring module is communicatively connected to the infusion pump control system to form a closed-loop control loop, enabling the infusion pump control system to dynamically adjust the infusion pump flow rate, infusion volume, or pause infusion based on the real-time monitored drug concentration distribution map.

14. The intracranial drug delivery system according to claim 13, characterized in that, Also includes: The data processing unit is connected to the infusion pump, the image navigation device integration module, the magnetic resonance imaging device, and the drug distribution quantitative monitoring module, respectively. The data processing unit is configured to execute the drug distribution quantitative monitoring algorithm and visualize the operating parameters and monitoring results.

15. A method for intracranial drug delivery, characterized in that, Using the intracranial drug delivery system of claim 12, the shearable buffer section of the convection-enhanced drug delivery catheter assembly is sheared according to the access distance measured intraoperatively by the neurosurgical navigation device (7), and the shearable buffer section is connected to the infusion line (3) through the connector.

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