Neurosurgical guide tubes

Abstract

A guide tube (4) is provided for use with a fluid transport tube to provide fluid access to the brain of a mammal. The guide tube (4) is configured to be inserted into the brain and comprises a through-hole for the fluid transport tube to pass through and a distal end (18). The distal end (18) of the guide tube includes a sealing region (70) configured to compress the surrounding brain tissue to form an anti-backflow seal around the distal end (18) of the guide tube. The sealing region comprises a decompression region (72) where the compression of the brain tissue is lower than the compression of the brain tissue in both the proximal and distal adjacent regions. Furthermore, a neurosurgical device comprising the guide tube and a method for convection-enhanced delivery of an injectable fluid into the brain parenchyma using the guide tube are disclosed.

Description

Technical Field

[0001] The present invention relates to an apparatus and method for use in neurosurgical operations. In particular, the present invention relates to an apparatus for use in delivering a therapeutic agent directly into the brain parenchyma by injection, and a method for delivering a therapeutic agent.

Background Art

[0002] Treatment of neurological diseases can be hindered by the presence of the blood-brain barrier. The blood-brain barrier can make it difficult to develop therapeutic agents that can be delivered from the systemic circulation into the brain parenchyma. There may be cases where it is desirable to deliver a therapeutic agent to a specific region of the brain (a "brain volume" or "target volume"). In order to reduce unwanted side effects, it is desirable to obtain an appropriate concentration of the therapeutic agent within the target volume while minimizing exposure of the therapeutic agent to the rest of the brain.

[0003] Convection-enhanced delivery (CED) is a method of targeted delivery of a therapeutic agent to a specific brain volume by controlling the injection of the therapeutic agent delivered into the brain parenchyma within a fluid using a very small cannula or tube (often referred to as a microcatheter in the art). One or more ports are present at the distal end of the cannula, and an infusion fluid containing the therapeutic agent can be discharged from the catheter and injected into the target brain volume. In order to overcome the local pressure of the target brain volume and thereby enable the infusion fluid to effectively flow into the target brain volume, it is necessary to achieve a continuous pressure gradient at the port.

[0004] The use of CEDs presents challenges because the fluid flowing from a cannula follows the path of least resistance. Typically, the path of least resistance causes the fluid to flow back along the interface between the cannula and the tissue rather than being delivered to the tissue as desired, resulting in so-called backflow. To control backflow and deliver the fluid to the target volume of tissue, CED cannulas typically have a rapid change in diameter ("step") towards the distal end. For example, the distal end of a cannula has a diameter of less than 1 mm in the short section leading to the most distal end, and the diameter gradually increases to 1.5-2.5 mm in the rest of the cannula. The small-diameter distal end, when inserted with minimal trauma, forms a tissue seal around the cannula, minimizing backflow along the interface. The change in diameter at the step compresses the tissue when inserted into the brain, further suppressing backflow.

[0005] Careful control of the flow rate (typically in the range of 3-5 microliters per minute) facilitates the flow of the injector into the tissue, prioritizing it over backflow. Higher flow rates tend to increase backflow, and the backflowing injector tends to pass over the ridge and flow back along the interface between the cannula and brain tissue, even at the larger diameter portion of the cannula. Once overcoming the ridge in this way, the injector enters a low-resistance path through the large circumferential space surrounding the larger diameter portion of the cannula, resulting in a reduced intended distribution of the injector within the target volume.

[0006] The design of the anti-reflux step varies depending on the CED cannula. Cannulas described in EP1482851B1 and US2010 / 0217228A1 have a single step. WO2007 / 024841A2 provides cannulas with multiple steps, and WO2014 / 016591 has a recessed step.

[0007] In addition to the design of the step, the length of the cannula that extends beyond the step to its distal end is a crucial factor in determining both the volume and shape of the distribution of the injectable fluid injected into the brain tissue. Short-step cannulas (i.e., cannulas that are short in length and small in diameter) have a small distribution volume (Vd) and are generally spherical. As the length of the small-diameter section increases, Vd increases, becoming more oval, then cylindrical, and finally pear-shaped with a bulbous distal end. When the distribution radius of the fluid convecting in the brain exceeds the distribution radius of the compressed tissue area at the step, the injectable fluid tends to enter a low-resistance path along the larger diameter section of the cannula and backflow from the target volume. This imposes limitations on the target Vd.

[0008] Therefore, treating clinically meaningful tissue volumes with a fixed step length configuration can be problematic. When using cannulas with short, fixed step lengths, continuous injections are required at various points along the trajectory to the brain to fill elongated tissue volumes. Similarly, multiple passes are necessary to fill large, spherical structures within the brain. Conversely, when filling smaller targets with catheters having relatively long "step lengths," it can be difficult to keep the treatment within the target. Therefore, the ability to adjust the step length for each target is a significant advantage.

[0009] In most cases of CNS (central nervous system) disease treatment with CED, multiple cannulas need to be implanted to achieve the desired range of fluid infusion into the brain tissue. Once the desired target volume and shape are defined from MRI images, the number and orientation of cannulas required to fill the volume are determined by understanding the distribution shape and volume achievable with the cannulas to be used. It is also important to perform MRI imaging during or immediately after the injection of the therapeutic agent to confirm that the injected agent has covered the specified therapeutic volume.

[0010] When using a rigid cannula, it is fixed within a stereotactic frame while the injection is being administered. In this configuration, the stereotactic frame must be MRI-compatible and thin enough to fit within the imaging coil. Typically, additional cannula placement and injection are required after the initial injection is complete. Therefore, such procedures are relatively time-consuming, and the prolonged anesthesia and fixation may expose the patient to greater risk.

[0011] Alternative procedures employing multiple cannula trajectories utilize flexible cannulas that are implanted and fixed in the skull. The flexible cannula tubes extending from the skull can be attached to a low-profile cranial fixation device. This facilitates safe transfer to an MRI scanner and allows for simultaneous injection while the patient is awake for neurological evaluation. When flexible cannulas are used, a stereotactic frame is not required during injection. While flexible cannulas can be removed after injection is complete, they may, in some cases, be left in place for repeated injections over days, weeks, or months.

[0012] The use of flexible cannulas is described in EP1482851B1, EP2601997A1, EP2819739B1 and WO2014 / 016591. In these configurations, the distance between the distal end of the cannula and the anti-reflux step can be adjusted. In all cases, the flexible cannula has a proximal hub and is cut to the length required for insertion into the target point in the brain. Once inserted into the implanted guide tube and further cut to the required length, the hub of the cannula acts as a stopper when it engages with the proximal head of the guide tube, which is fixed to the skull. The cannula extends beyond the guide tube, and the step created by the change in diameter from the cannula to the guide tube provides resistance to the backflow of the injectable fluid.

[0013] In the general procedure for implanting a flexible cannula, as described in EP1482851B1, EP2601997A1, and EP2819739B1, a contoured hole is drilled in the skull along a selected trajectory, guided by stereotactic or image-guided robotics. The probe is then passed through the hole to the intended distal end of the guide tube and withdrawn, leaving a pathway in the brain tissue. The guide tube is cut to length and positioned on the delivery probe so that the rounded tip of the delivery probe extends slightly beyond the distal end. The guide tube (on the delivery probe) is then inserted along the pre-created pathway until the proximal end head is pushed into the hole formed in the skull. The probe is then advanced to the intended position of the cannula target and withdrawn, leaving a trajectory through the tissue adjacent to the hole in the guide tube.

[0014] A cannula, connected to an infusion pump and delivering the infusion fluid at a low flow rate, is inserted into a guide tube, exits the distal end of the guide tube, and travels through a pre-formed pathway within the tissue. Once inserted into the brain, the cannula is filled with the infusion fluid, and the slow, continuous infusion into the cannula minimizes tissue damage during transit. As the therapeutic fluid is delivered through the distal port of the cannula, it typically follows the path of least resistance and backflows along the cannula-tissue interface before reaching the tissue area compressed by the distal end of the guide tube. Local pressure at the interface acts to suppress further backflow, and the infusion fluid is preferentially delivered radially into the tissue.

[0015] The above devices have potential drawbacks. Depending on the insertion method, microtrauma to tissue may occur, creating a less resistant pathway for the injected fluid and potentially hindering backflow control at the guide tube-tissue interface. Inserting the guide tube into a pre-formed pathway in the brain may cause the cutting edge of its distal end to sever tissue, potentially forming a circumferential column of fragmented tissue. The force required to push the head of the guide tube / delivery probe into a pre-formed hole in the skull is also transmitted to the distal end of the guide tube / delivery probe, potentially increasing localized tissue trauma in the step area.

[0016] Furthermore, once the cannula is inserted into the guide tube, it tends to act as a piston, pushing a column of air forward. Even with suction applied at the proximal end of the guide tube, it is difficult to remove the air from the narrow space between the cannula and the guide tube. When air is injected into the brain, it tears brain tissue and forms space-occupying lesions near the step that controls the reflux. In the short term, this may disrupt the intended distribution pattern of the injected fluid, but once the air is absorbed, the remaining cavity becomes a low-resistance pathway at that step, which can increase undesirable reflux.

[0017] EP3119310B1 describes a guide tube with an internal profile configured to provide a fluid return path for carrying fluid pushed out from within the guide tube during catheter insertion. Such a path can guide or expel air during catheter insertion. However, creating a profile with an internal channel large enough to facilitate air removal increases the overall dimensions of the guide tube. A larger diameter of the guide tube may increase the risk of trauma during insertion. Narrowing the channel between the guide tube and the cannula may also cause airflow to be obstructed by surface tension due to the presence of fluid.

[0018] International patent application WO2014 / 016591A1 discloses a recessed step structure in which the guide tube has an internal recess that compresses the internal tissue. The internal recess provides a step function intended to more effectively compress the tissue in order to restrict the flow of the injectable fluid along the interface between the cannula and the tissue. However, with such a structure, inserting the guide tube can cause abrasion of a portion of the brain tissue. Localized tissue trauma can cause neurological defects or bleeding if it is in a critical part of the brain.

[0019] A further potential problem with known CED devices, particularly those implanted chronically, is brain movement. Because the brain moves within the skull, fixing the cannula or associated guide tube to the skull can cause the tube or cannula to move relative to brain tissue. This can result in localized tissue trauma, particularly at regurgitation resistance steps, leading to local vacuolation and the formation of low-resistance pathways that tend to enhance rather than resist regurgitation. [Overview of the Initiative] [Problems that the invention aims to solve]

[0020] Given the difficulties mentioned above, there is still a need for CED devices that offer improved backflow resistance and reduced trauma during use. [Means for solving the problem]

[0021] According to a first embodiment, a guide tube is provided for use with a fluid transport tube to provide fluid access to the brain of a mammal. The guide tube is configured to be inserted into the brain and comprises a through-hole for the fluid transport tube to pass through, and a distal end. The distal end of the guide tube includes a sealing region configured to compress the surrounding brain tissue to form a backflow prevention seal around the distal end of the guide tube. The sealing region comprises a decompression region in which the compression of the brain tissue is lower than the compression of the brain tissue in both the proximal and distal adjacent regions.

[0022] The reduced pressure region creates an area where the backflowing fluid is trapped, and because it is necessary for the fluid to bypass multiple high-compression regions to flow back along the outer surface of the guide tube, the sealing effect at the distal end of the guide tube is improved. As a result, it is not necessary to create a large step in the outer diameter of the guide tube, and backflow prevention can be achieved with a guide tube that has a smaller outer diameter and places less burden on brain tissue than conventional backflow prevention cannulas.

[0023] Optionally, the seal area comprises a plurality of decompression areas. The plurality of decompression areas further enhance the effectiveness of the seal provided at the distal end of the guide tube and reduce the risk of backflow.

[0024] Optionally, the plurality of decompression areas are arranged at equal intervals along the length of the guide tube. This realizes a regular structure and a consistent change in compression along the guide tube.

[0025] Optionally, the interval between the decompression areas is at most 2 mm, preferably at most 1.5 mm, more preferably at most 1 mm. Maximizing the interval between the areas shortens the length of the guide tube where fluid may flow back.

[0026] Optionally, the decompression area is provided over at least 5% of the length of the guide tube. Optionally, the decompression area is provided over at least 2 mm of the length of the guide tube. Providing an area that exceeds the minimum length of the guide tube ensures sufficient minimum seal performance.

[0027] Optionally, at least one decompression area is at most 20 mm away from the most distal end of the guide tube. Optionally, at least one decompression area is at most 25% of the length of the guide tube away from the most distal end of the guide tube. By providing a decompression area within a certain distance from the distal end, fluid cannot flow back beyond a large length of the guide tube.

[0028] Optionally, the decompression area is provided by a groove on the outer surface of the guide tube or between protrusions from the outer surface of the guide tube. The groove or protrusions provide a convenient and easy way to provide a change in pressure along the outer surface of the guide tube.

[0029] As an option, the depth of the groove is at most 0.5 mm, or the height of the protrusion is at most 0.5 mm. As an option, the depth of the groove is at least 0.1 mm, or the height of the protrusion is at least 0.1 mm. Within this dimensional range, sufficient changes occur in the compression of the surrounding tissue, and good sealing performance for preventing backflow is obtained.

[0030] As an option, the groove or the protrusion extends over the entire circumference of the guide tube. Thereby, good sealing protection against backflow is provided at all points around the guide tube, and the backflow is further minimized.

[0031] As an option, the outer surface of the guide tube is configured to contact the brain tissue after the guide tube is inserted into the brain. Thereby, the space between the guide tube and the brain tissue is tightly sealed, and backflow is prevented.

[0032] As an option, the outer surface of the guide tube is provided with a lubricating coating such as parylene or PTFE. Thereby, the ease of inserting the guide tube into the brain is improved, and the shearing force and trauma to the brain tissue when inserting the guide tube into the brain are reduced.

[0033] As an option, the distal end of the guide tube is round, bullet-shaped or conical. Thereby, the damage and trauma to the brain tissue during the insertion of the guide tube are reduced.

[0034] As an option, the diameter of the distal end of the guide tube is at most 2.5 mm, preferably 1.8 mm, more preferably at most 1.6 mm, and most preferably at most 1.3 mm. This dimensional range is particularly suitable for enabling effective injection while reducing trauma to the tissue.

[0035] Optionally, the diameter of the through-hole in the guide tube is 0.2 mm to 1 mm, preferably 0.4 mm to 0.7 mm, and more preferably 0.5 mm to 0.6 mm. This allows a thin cannula with dimensions appropriate for effective tissue injection to be passed through the tissue via this through-hole.

[0036] As an option, the guide tube is a rigid guide tube containing a rigid material such as ceramics like zirconia ceramic, metals like titanium, or rigid plastics like polyether ether ketone. These materials are biocompatible, do not produce significant image artifacts in MRI, and possess properties suitable for the rigidity requirements of the guide tube. This prevents the guide tube from deflecting or distorting during insertion, allowing it to reach the target more reliably and accurately.

[0037] Optionally, the length of the rigid guide tube is 50mm to 300mm, preferably 100mm to 250mm. This allows the guide tube to reach common targets in the human brain when held by an external device, such as a stereoguide or robotic guide.

[0038] Optionally, the rigid guide tube has a proximal end configured to be guided and / or held by a stereotactic guide or robotic guide while the guide tube is inserted into the brain and / or while the injectable fluid is delivered to the brain using the guide tube. This allows the guide tube to be inserted directly into a desired target location in the brain, for example, during critical procedures.

[0039] Optionally, the proximal end of the rigid guide tube has a larger diameter than the distal end. This allows the guide tube to be held more conveniently and securely by a stereoguide or robotic guide. Optionally, the diameter of the proximal end of the guide tube is up to 7 mm, preferably up to 6 mm, and more preferably up to 5 mm.

[0040] Optionally, the guide tube is a cuttable guide tube, and the material and / or thickness of the guide tube is such that it can be cut by hand with a knife. This allows the guide tube to be easily adjusted to the precise length during the procedure and before insertion.

[0041] Optionally, the length of the scalable guide tube is 25 mm to 150 mm. Preferably, the maximum length of the scalable guide tube is 110 mm. For example, the length is between 50 mm and 110 mm. This allows the guide tube to reach a typical target volume in the human brain, for example, if the proximal end is fixed to the skull.

[0042] As an option, the severable guide tube is a multilayer tube with inner and outer layers having different properties, for example, the layers are made of plastic.

[0043] Optionally, the severable guide tube includes a porous layer that allows air to pass through, and the porous layer contains a hydrophobic material. Preferably, the porous layer is in fluid communication with the through-holes of the guide tube. This allows air to be removed when the fluid transfer tube passes through the guide tube, reducing damage to the tissue due to air compression. The hydrophobic material prevents the porous material from being clogged by the liquid, maintaining permeability. Optionally, the hydrophobic material is superhydrophobic. Optionally, the porous layer contains at least one of sintered PTFE, sintered polyurethane, ePTFE, silicone foam, polyurethane foam, shape memory polymer, microporous hollow extruded polymer fibers, or electrospun polymers. Optionally, the microporous hollow extruded polymer fibers and / or electrospun polymers contain at least one of polytetrafluoroethylene, polyvinylidene fluoride, polyurethane, polypropylene, and copolymers thereof.

[0044] Optionally, the porous layer may include heterogeneous materials with different stiffnesses and / or multiple materials with different stiffnesses. This is advantageous when the porous layer of the guide tube is made of a material that does not have sufficient columnar strength to maintain its length when the guide tube is inserted into brain tissue using a probe. A variety of stiffnesses or multiple different stiffnesses can provide support with a stiffer layer compared to a more flexible porous material.

[0045] Optionally, the rigidity of the guide tube can be increased at or near the through-hole. This helps to support the fluid transfer tube that is passed through the guide tube.

[0046] Optionally, the porous layer includes at least an inner layer and an outer layer, with the inner layer being more rigid than the outer layer and more porous to air. Making the rigider inner layer permeable improves air expulsion from the guide tube's through-holes.

[0047] Optionally, the inner layer may have multiple holes penetrating it. This is a convenient way to provide porosity without compromising the rigidity of the hard layer.

[0048] Optionally, the inner layer is the innermost layer of the guide tube and provides the surface of the through-hole. This helps to support the cannula that is passed through the guide tube.

[0049] Optionally, the inner layer may include at least one of the following: polyether ether ketone; nylon; polyurethane; polyester; fluoropolymers such as polytetrafluoroethylene; polymer perfluoroethers such as perfluoroalkoxy alkanes, polyvinylidene difluoride, and fluorinated ethylene propylene; liquid crystal polymers; and mixtures or copolymers thereof. These materials possess properties suitable for an inner layer, such as rigidity.

[0050] Optionally, the inner layer is manufactured by a process including at least one of the following: sintering; extrusion with micro-particle leaching, micro-perforation of the tube by drilling or laser; weaving, braiding, or electro-spinning polymer fibers around a cylindrical mold to form a tube of porous polymer material; and 3D printing of the polymer in a porous form. These manufacturing methods are suitable for forming the narrow diameter structure required for the inner layer of the guide tube.

[0051] Optionally, the porous layer is the outermost layer of the guide tube. This facilitates manufacturing, for example, when forming the guide tube from a sintered polymer or depositing the porous layer onto a harder inner layer. This also promotes biointegration of the guide tube in chronic implantation by allowing tissue to penetrate the pores of the porous outer layer.

[0052] Optionally, the guide tube further comprises a fluid-impermeable coating layer provided on the porous layer. Optionally, the coating layer is lubricating. Optionally, the coating layer includes, for example, a heat-shrinkable tube comprising a lubricating and fluid-impermeable polymer. Suitable heat-shrinkable polymers include fluorinated ethylene propylene (FEP), polyethylene terephthalate (PET), polyolefins, and polytetrafluoroethylene (PTFE).

[0053] Optionally, the reduced pressure region may be provided by a coating layer. For example, the coating layer may include a heat-shrinkable tube applied over a porous layer and having a series of annular thickenings or grooves along its axis.

[0054] As an option, the guide tube is flexible. This allows the guide tube to adapt to the movement of the brain relative to the skull, especially when the guide tube is chronically implanted.

[0055] Optionally, at least the proximal portion of the guide tube is elastically deformable along the axial direction. This prevents the distal end of the guide tube from moving so much that it deviates from the intended target, allowing the guide tube to adapt to the movement of the brain within the skull.

[0056] Optionally, the guide tube comprises at least an inner layer and an outer layer, with the inner layer being more rigid than the outer layer and the outer layer being elastically deformable, and the inner layer not extending to the proximal part of the guide tube. By creating a region where the inner layer is absent, the outer layer in that region can deform to accommodate the movement of the brain relative to the skull.

[0057] Optionally, the guide tube comprises at least an inner layer and an outer layer, with the inner layer being more rigid than the outer layer and the outer layer being elastically deformable, and the inner layer being configured to provide a spring at the proximal end of the guide tube. The spring configuration ensures the continuity of the inner layer, improving stability while also accommodating relative movements between the brain and the skull.

[0058] Optionally, the proximal end of the guide tube includes an expansion section configured to be fixed into a trepanation hole in the skull. This creates a seal between the guide tube and the skull, preventing leakage of fluid from the brain and entry of substances into the brain.

[0059] Optionally, the enlarged section includes a larger diameter section configured to engage with a guide hub for fixation to the skull. This allows for secure engagement and sealing between the guide tube and the guide hub.

[0060] Optionally, the larger diameter section may be overmolded onto a harder inner layer. For example, the larger diameter section may be overmolded with PEEK onto a perforated PEEK inner tube, or with polyurethane onto an air-porous polyurethane inner tube.

[0061] Optionally, a fluid seal is formed between the guide tube and the guide hub by engaging the larger diameter portion of the guide tube with the guide hub. This prevents leakage of cerebrospinal fluid or other injectable fluids from the guide tube, and also prevents unwanted substances from entering the skull.

[0062] Optionally, the guide tube has an elastically deformable outer layer, and the engagement between the larger diameter section of the guide tube and the guide hub involves compression of the outer layer. This reduces the need for other sealing means such as O-rings, allowing for a smaller device size and reduced complexity.

[0063] Optionally, the diameter of the through-hole in the guide tube within the large-diameter section increases towards the proximal end of the large-diameter section. This makes it easier to insert the fluid transfer tube, such as a cannula, into the guide tube by guiding it through the through-hole.

[0064] Optionally, the larger diameter section features a non-compliant core located inside the outer layer. This provides a secure proximal section for inserting the guide tube and engaging it with the guide hub.

[0065] Optionally, the non-compliant core is configured to ensure a gas path through it. This increases the surface area from which gas can be vented, thereby enhancing the gas venting capacity of the guide tube. Optionally, the non-compliant core is constructed from a porous material such as sintered polyurethane or PEEK. This facilitates the venting of air when the fluid transfer tube is inserted into the through-hole of the guide tube. Alternatively or additionally, the non-compliant core may have air vent channels that penetrate it to facilitate the venting of air from the porous layer of the guide tube into the atmosphere.

[0066] Optionally, the non-compliant core is placed inside the porous layer. This allows the porous layer to vent gases around the non-compliant core.

[0067] Optionally, the non-compliant core is positioned outside the inner layer. This allows the non-compliant core to be fixed to a rigid inner layer without affecting the shape and arrangement of the inner layer in the proximal region.

[0068] Optionally, the inner layer does not extend to the nearest end of the large diameter section, and optionally, the inner layer extends to a maximum of 80%, preferably a maximum of 60%, of the large diameter section. This allows the non-compliant core to more completely determine the characteristics of the large diameter section. This also exposes a larger portion of the non-compliant core to the through-hole of the large diameter section, which can be particularly advantageous if the non-compliant core is configured to vent gases.

[0069] According to a second embodiment, a neurosurgical device is provided comprising a guide tube including a large-diameter portion configured to engage with a guide hub for fixation to the skull, and a guide hub for fixing the guide tube to the patient's skull before insertion into the brain, the guide hub having a passage through which the guide tube passes. The guide hub provides a fixation point on the skull to which the guide tube can be inserted and fixed. This can be convenient for patients requiring regular treatment, as the guide hub and optionally the guide tube can be left in place between injection procedures.

[0070] Optionally, the device further comprises a fluid transfer tube, preferably a cannula, configured to be inserted into a through-hole in the guide tube. The fluid tube can be used to introduce the injectable fluid and can be easily connected to an external pump or syringe.

[0071] According to a third embodiment, a neurosurgical device is provided comprising a guide tube of the first embodiment and a fluid transfer tube (preferably a cannula) configured to be inserted into a through-hole of the guide tube. Providing a guide tube and a fluid transfer tube is convenient because they can be adapted to each other for any desired procedure. The fluid tube can be used to introduce an injectable fluid and can be easily connected to an external pump or syringe.

[0072] Optionally, the fluid transfer tube is equipped with a depth control stopper configured to engage with the proximal end of the guide tube to form a fluid seal between the fluid transfer tube and the guide tube, and optionally, the depth control stopper engages with the larger diameter portion of the proximal end of the guide tube. This ensures that the fluid transfer tube is inserted to the correct depth, thereby allowing the fluid to reach the correct area of ​​the brain.

[0073] Optionally, if the guide tube is made of a rigid material, or if the guide tube has a proximal end configured to be guided and / or held by a stereotactic or robotic guide during insertion of the guide tube into the brain, the fluid transfer tube may be made of a rigid material, such as fused silica. Optionally, if the guide tube is severable and / or flexible, the fluid transfer tube may also be flexible. This ensures that the properties of the fluid transfer tube match those of the guide tube, and that both are handled similarly and correctly during insertion and use.

[0074] Optionally, a second or third embodiment of the device further comprises a probe configured to be inserted into brain tissue, the probe comprising a rod having a round or conical distal end, and a spike extending axially from the distal end of the rod, the spike having a narrower diameter than the rod, and the most distal end of the spike being configured to incise brain tissue. This probe can be used to create a pathway in the brain before inserting a guide tube.

[0075] Optionally, the apparatus in a second or third embodiment further comprises a delivery probe configured to be inserted into a through-hole in the guide tube, the distal end of which is configured to cut brain tissue. The delivery probe allows the guide tube to be easily delivered to the target location, in particular when the guide tube is flexible and may deform if inserted into the brain without the delivery probe.

[0076] According to a fourth aspect, a neurosurgical device is provided comprising a guide tube of the first aspect and a probe configured to be inserted into brain tissue. The probe comprises a rod having a round or conical distal end and a spike extending axially from the distal end of the rod, the diameter of which is narrower than that of the rod, and the distal end of the spike is configured to incise brain tissue. The device can be used to create a pathway in the brain using the probe before inserting the guide tube, and then to insert the guide tube.

[0077] According to a fifth aspect, a neurosurgical device is provided comprising a guide tube according to the first aspect and a delivery probe configured to be inserted into a through-hole of the guide tube, wherein the distal end of the delivery probe is configured to incise brain tissue. The delivery probe allows the guide tube to be easily delivered to a target location, in particular when the guide tube is flexible and may deform if inserted into the brain without the delivery probe.

[0078] A sixth aspect provides a method for implanting a guide tube for convective-enhanced delivery of an injectable fluid into the brain parenchyma. The method comprises inserting the guide tube into the brain until the distal end of the guide tube reaches a planned location in the brain, the guide tube comprising a through-hole for passing a fluid transport tube and a distal end including a sealing region, the method further comprises compressing brain tissue adjacent to the sealing region to form a backflow-inhibiting seal around the distal end of the guide tube, and forming a decompression region in which the compression of the brain tissue is lower than the compression of the brain tissue in both the proximal and distal adjacent regions of the decompression region.

[0079] As described above, using a guide tube makes it possible to embed a system in which the reduced pressure region provided by the guide tube suppresses backflow of the fluid introduced through the fluid transfer tube.

[0080] Optionally, this method further includes inserting a probe into the brain parenchyma to form a guide tube pathway extending to the intended location before inserting the guide tube into the brain, wherein the guide tube has at least the diameter of the probe, and inserting the guide tube into the brain includes inserting the guide tube into the guide tube pathway. Thus, forming the pathway using the probe first can reduce the trauma to brain tissue that would result from advancing the guide tube into the brain.

[0081] Optionally, the probe comprises a rod with a round or conical distal end and a spike extending axially from the distal end of the rod, the spike having a narrower diameter than the rod, and the most distal end of the spike being configured to cut through brain tissue. This spike allows for the opening of a pathway while minimizing trauma to brain tissue.

[0082] Optionally, this method further involves cutting the guide tube to the desired insertion length relative to fixation points within the skull before inserting it into the brain. This means that the guide tube is provided in the exact required length based on on-site measurements, rather than relying on prior estimations.

[0083] According to a seventh aspect, a method is provided for convection-enhanced delivery of an injectable fluid into the brain parenchyma. This method includes implanting a guide tube in the brain using the method of a sixth aspect; advancing a delivery probe through a through-hole along the axis of the guide tube to form a fluid transport tube pathway extending from the distal end of the guide tube; passing a fluid transport tube through the through-hole of the guide tube and through the fluid transport tube pathway into the brain; and delivering an injectable fluid to the brain via the fluid transport tube.

[0084] Optionally, guide tube insertion is performed with the delivery probe inside the through-hole, with the distal end of the delivery probe extending to or slightly beyond the distal end of the guide tube. This may help maintain the shape and rigidity of the guide tube during insertion.

[0085] Optionally, the diameter of the fluid transfer tube path is narrower than the diameter of the guide tube path. This creates a step at the distal end of the guide tube, improving sealing and reducing backflow.

[0086] According to an eighth aspect, a method is provided for convection-enhanced delivery of an injectable fluid into the brain parenchyma. This method comprises implanting a guide tube in the brain using the method of the sixth aspect, wherein inserting the guide tube into the brain comprises inserting the guide tube together with a fluid transfer tube in a through-hole, preferably providing positive pressure of the injectable fluid in the fluid transfer tube during insertion of the guide tube, and the method further comprises delivering the injectable fluid into the brain via the fluid transfer tube. [Brief explanation of the drawing]

[0087] Hereinafter, embodiments of the present invention will be described as non-limiting examples with reference to the accompanying drawings. [Figure 1] Figure 1 is a magnified view of the distal end of the guide tube and cannula. [Figure 2] Figure 2 is a cross-sectional view of the distal end of the guide tube. [Figure 3] Figure 3 shows a fluid transfer tube or cannula. [Figure 4] Figure 4 shows an insertion guide for holding the guide tube, for use with a stereotactile guide. [Figure 5] Figure 5 is a cross-sectional view of a guide tube with a sealing region at its distal end and a cannula incorporated within the through-hole, for use with the insertion guide shown in Figure 4. [Figure 6]Figure 6 is an enlarged cross-sectional view of a portion of the sealing area. [Figure 7] Figure 7 is a cross-sectional view of a guide tube having a perforated inner layer with a sealing region at the distal end and a helically cut proximal portion. [Figure 8] Figure 8 shows the inner layer of the guide tube in Figure 7. [Figure 9] Figure 9 is a cross-sectional view of a guide tube having a sealing region at the distal end and including a perforated inner layer. [Figure 10] Figure 10 shows the inner layer of the guide tube in Figure 9. [Figure 11] Figure 11 shows the guide tubes of Figures 8 and 10 with the outer layer attached. [Figure 12] Figure 12 shows the guide hub for fixation to the skull. [Figure 13] Figure 13 is a cross-sectional view of the guide hub shown in Figure 12. [Figure 14] Figure 14 is a cross-sectional view of an assembled neurosurgical device. [Figure 15] Figure 15 shows the assembled neurosurgical device from Figure 14. [Figure 16] Figure 16 shows a bubble vent attached to the proximal end of a fluid transfer tube. [Figure 17] Figure 17 shows an exploded view of the bubble vent. [Figure 18] Figure 18 shows an alternative design for the bubble vent. [Figure 19] Figure 19 shows an exploded view of the bubble vent shown in Figure 18. [Figure 20] Figure 20 shows a cross-sectional view of the bubble vent shown in Figures 18 and 19. [Figure 21] Figure 21 shows a magnified view of the bubble vent in use as shown in Figure 20. [Figure 22] Figure 22 shows the probe used to create a pathway in the brain through which a guide tube can be inserted. [Modes for carrying out the invention]

[0088] To address the limitations of the conventional guide tubes described above, the present invention provides a guide tube 4 as shown in Figure 1. Figure 1 shows the distal end 18 of the guide tube 4. The guide tube 4 is used in conjunction with a fluid transfer tube 6, shown in Figure 3 and described in more detail below. The fluid transfer tube 6 (e.g., a cannula) is intended to provide fluid access to enable the transfer of fluid, for example, into or from the brain of a mammal. The guide tube 4 is configured to be inserted into the brain. The guide tube 4 and the fluid transfer tube 6, together with other components described below as necessary, are referred to as a cannula assembly, a neurosurgical cannula assembly, or a neurosurgical device.

[0089] The guide tube 4 is configured to be inserted into the brain coaxially with the trajectory to the target in the brain. The trajectory is established by image guidance and can be defined between the entry point in the skull and the target. The target can be a specific region or location in the mammalian brain. The distal end 18 of the guide tube 4 can be inserted into a predetermined position in the brain along the trajectory to the target. This predetermined position may not be the treatment target point itself, but a point along the trajectory proximal to the target. This is because the fluid transfer tube 6 generally extends beyond the distal end 18 of the guide tube 4. The proximal end 28 of the guide tube 4 can be guided and held by stereoguidance or robotic guidance during use.

[0090] The diameter of the distal end 18 of the guide tube 4 is a maximum of 2.5 mm, preferably 1.8 mm, more preferably 1.6 mm or less, and most preferably 1.3 mm or less. The guide tube 4 may have a larger diameter section at its proximal end, as will be further described below. The maximum dimensions of the guide tube 4 described herein do not usually include the larger diameter section (if any).

[0091] The guide tube 4 may be made of a ceramic such as zirconia ceramic, a metal such as titanium or stainless steel, or a plastic such as polyether ether ketone. The preferred material may vary depending on the specific application, as will be further described below.

[0092] As shown in the enlarged view of Figure 1, the distal end of the guide tube 4 may be round, bullet-shaped, or conical. This reduces trauma to brain tissue when inserting the guide tube 4.

[0093] The outer surface of the guide tube 4, particularly the outer surface of the distal end 18, can be configured to come into contact with brain tissue after the guide tube 4 is inserted into the brain. To improve tissue adhesion, tissue integration ability, lubricity, or other desirable properties, at least the outer surface of the guide tube 4 may be provided with a lubricating coating. For example, the outermost surface may be post-treated, such as by plasma treatment, or may be coated with an appropriate coating to impart desired properties. For example, a lubricating coating of parylene or polytetrafluoroethylene (PTFE) can be used to reduce the shear force on brain tissue when the guide tube 4 is inserted into the brain. Alternatively, a lubricating heat-shrinkable plastic tube can be applied to the outer surface of the guide tube. For example, the heat-shrinkable tube may be made of PTFE, FEP, PET, or polyolefin.

[0094] Figure 2 shows a cross-sectional view of the distal end 18 of an exemplary guide tube 4. The guide tube 4 is provided with a through-hole 30 for passing a fluid transfer tube 6, such as a cannula. The diameter of the through-hole 30 is 0.2 mm to 1 mm, preferably 0.4 mm to 0.7 mm, and more preferably 0.5 mm to 0.6 mm. Advantageously, the through-hole 30 of the guide tube 4 is sized to fit tightly to the outer surface of the fluid transfer tube 6. This tight fit prevents a pathway for backflow of the injected fluid from the brain.

[0095] Figure 3 shows an example of a fluid transfer tube 6. The fluid transfer tube 6 is configured to allow the transfer of fluid to or from the mammalian brain. In particular, the fluid transfer tube 6 is used to transfer fluid to or from a target brain volume. The fluid transfer tube 6 is configured to be inserted into the brain by being inserted into a through-hole 30 of a guide tube 4. The fluid transfer tube 6 is routed along the through-hole 30 from the proximal end 28 to the distal end 18 of the guide tube 4. The fluid transfer tube 6 typically protrudes beyond the distal end 18 of the guide tube so that the distal end 10 of the fluid transfer tube 6 is positioned at the target in the brain.

[0096] The outer diameter of the fluid transfer tube 6 is 0.4 mm to 0.7 mm, preferably 0.5 mm to 0.6 mm, for example, 0.5 mm. The through hole (or inner diameter) of the fluid transfer tube 6 may be in the range of 0.1 mm to 0.4 mm. The length of the fluid transfer tube 6 may be at least 100 mm. In general, the fluid transfer tube 6 may have at least the length of the guide tube 4.

[0097] The fluid transfer tube 6 may be formed from a rigid material, such as fused silica, a metal such as titanium or stainless steel, or a rigid biocompatible plastic such as polyetheretherketone (PEEK). Alternatively, the fluid transfer tube 6 may be formed from a flexible material, such as a flexible biocompatible plastic. The choice between using a rigid or flexible fluid transfer tube 6 can be made based on the specific application and characteristics of the guide tube 4. Preferably, the distal end 10 of the fluid transfer tube 6 is round, conical, or bullet-shaped to minimize tissue damage during insertion, as described for the guide tube 4.

[0098] The fluid transfer tube 6 may have a fluid connector at its proximal end, configured to connect to a fluid injection line or directly to a syringe and injection pump. The fluid transfer tube 6, particularly its proximal end, may include a depth control stopper 40 configured to engage with the proximal end 28 of the guide tube 4 to form a fluid seal between the fluid transfer tube 6 and the guide tube 4. The depth control stopper 40 may engage with the larger diameter portion of the proximal end 28 of the guide tube 4. The engagement of the distal surface of the depth control stopper 40 on the fluid transfer tube 6 with the proximal surface of the larger diameter portion of the guide tube 4 can form a fluid seal. The position of the depth control stopper 40 along the length of the fluid transfer tube 6 may be adjustable. This allows adjustment of the length of the fluid transfer tube 6 that protrudes beyond the distal end 18 of the guide tube 4. Alternatively, the insertion depth of the fluid transfer tube can be adjusted by fixing the depth control stopper to the fluid transfer tube and using a knife to cut the fluid transfer tube to the desired length relative to the stopper.

[0099] In contrast to conventional devices, as shown in Figures 1 and 2, the distal end 18 of the guide tube 4 includes a sealing region 70. The sealing region 70 is configured to compress the surrounding brain tissue to form an anti-reflux seal around the distal end 18 of the guide tube 4. The sealing region 70 includes at least one decompression region 72, in which the compression of brain tissue is lower than that in both the proximal and distal adjacent focal regions. The proximal and distal adjacent regions are adjacent to the decompression region 72.

[0100] The guide tube 4 (or the cannula assembly in which the fluid transfer tube 6 is inserted into the guide tube 4 before insertion into the brain) is preferably passed through the brain along a pre-established pathway, as will be described in more detail below. Once the guide tube 4 enters the pathway, the pathway is gradually expanded to the larger diameter of the guide tube 4. As the fluid is delivered into the brain from its distal end through the fluid transfer tube 6, the fluid tends to follow the path of least resistance and return along the outer diameter of the fluid transfer tube 6 at the tissue interface. The backflowing fluid returns along the outside of the fluid transfer tube 6 towards the step 20 created by the change in diameter at the distal end 18 of the guide tube 4, which is the starting point from which the fluid transfer tube 6 extends. In the high-pressure region in the tissue immediately distal to the step 20 formed by the insertion of the guide tube 4, the tissue interface is compressed and backflow is suppressed. Due to the increase in fluid pressure, the fluid is delivered radially into the tissue.

[0101] However, as described above with respect to the prior art devices, this convection process continues until the pressure of the injected fluid exceeds the tissue pressure at step 20. Once the tissue pressure is exceeded, the fluid flows over step 20 and backflows to the outside of the guide tube 4, separating it from the target area, which is undesirable. By providing a sealing region 70 (for example, by using a series of circumferential grooves along the outer diameter of the guide tube 4 in Figures 1 and 2), a series of ring seals is substantially formed along the outside of the guide tube 4, providing cumulative resistance to fluid backflow along the length of the guide tube 4. This results in a cumulative resistance that is greater overall than the resistance generated by a single large step, thus providing backflow resistance even with a small outer diameter of the guide tube 4. This means that the guide tube 4 causes less trauma to brain tissue and is more effective at reducing backflow than currently available anti-reflux cannulas and guide tubes.

[0102] The seal region 70 may include one or more decompression regions 72. For example, the guide tube 4 shown in Figure 1 has a seal region 70 that includes six decompression regions 72. When the seal region 70 comprises multiple decompression regions 72, proximal adjacent regions and / or distal adjacent regions (regions where the compression of brain tissue is higher than that of the decompression region 72) may be shared among adjacent decompression regions 72. In other words, the proximal adjacent region of a first decompression region 72 may be the distal adjacent region of a second decompression region 72. Figure 6 shows a further enlarged view of a portion of the seal region 70. The multiple decompression regions 72 may be arranged at equal intervals along the length of the guide tube 4. The spacing between the decompression regions 72 is 2 mm or less, preferably 1.5 mm or less, and more preferably 1 mm or less. The spacing between the decompression regions 72 may be at least 0.5 mm. For example, the spacing may be 1 mm. The width W2 of each decompression region 72 may be at least 0.5 mm, and optionally at least 1 mm. The width of each decompression zone 72 is a maximum of 2 mm, with an optional maximum of 1.5 mm.

[0103] The depressurization region 72 may extend over at least 5% and / or at least 2 mm of the length of the guide tube 4. That is, the distance between the most distal depressurization region 72 and the most proximal depressurization region 72 may be at least 5% and / or at least 2 mm of the length of the guide tube 4. Preferably, the depressurization region 72 may extend over at least 10% and / or at least 4 mm of the length of the guide tube 4. In some situations, it may be advantageous to provide the depressurization region 72 over substantially the entire length of the guide tube 4, excluding the large diameter section 90 if one exists. For example, the depressurization region 72 can be provided over at least the entire distal portion 18 of the guide tube 4. The depressurization region 72 can be provided over all portions of the guide tube 4 except for the nearest 2 cm (excluding the large diameter section 90 if one exists), optionally 5 cm, and optionally 10 cm.

[0104] To most effectively suppress backflow, the decompression region 72 is preferably close to the distal end of the guide tube 4. At least one of the decompression regions 72 may be up to 20 mm, optionally up to 10 mm, optionally up to 5 mm, and further optionally up to 2 mm away from the distal end of the guide tube 4. At least one of the decompression regions 72 may be up to 25% of the length of the guide tube 4, optionally up to 15%, optionally up to 10%, and further optionally up to 5% away from the distal end of the guide tube 4.

[0105] The depressurization region 72 can be provided in any suitable manner. The seal region 70 may include one or more features relating to the outer diameter of the guide tube 4 configured to provide the depressurization region 72. These features may include a change in the outer diameter of the guide tube 4, so that the outer diameter of the guide tube 4 changes within the seal region 70. For example, in the guide tube of Figure 1, the depressurization region 72 is provided by grooves on the outer surface of the guide tube 4. That is, the outer diameter of the guide tube 4 in the depressurization region 72 is smaller than the outer diameter of the guide tube 4 in the rest of the distal region 18 outside the seal region 70. Alternatively or additionally, as shown in Figure 6, the depressurization region 72 can also be provided between projections 94 from the outer surface of the guide tube 4. That is, the outer diameter of the guide tube 4 in the proximal and distal adjacent regions on both sides of the depressurization region 72 can be larger than the outer diameter of the guide tube 4 in the rest of the distal region 18 outside the seal region 70.

[0106] The depressurization region 72 can also be provided by a combination of protrusions and grooves. Therefore, the depressurization region 72 may have a diameter smaller than the outer diameter of the guide tube, and regions with a diameter larger than the diameter of the guide tube may exist on both sides of the depressurization region 72.

[0107] The groove depth may be a maximum of 0.5 mm, or the height T2 of the projection 94 may be a maximum of 0.5 mm. The groove depth may be at least 0.1 mm, or the height T2 of the projection 94 may be at least 0.1 mm. Preferably, the groove depth is 0.2 mm, or the height T2 of the projection 94 is 0.2 mm.

[0108] The groove or projection 94 can extend around the entire circumference of the guide tube 4. This causes the reduced pressure region 72 to extend around the entire circumference of the guide tube 4, thereby improving the sealing effect of the sealing region 70.

[0109] The guide tube 4 may be a rigid guide tube that is inserted into a predetermined position in the brain along a trajectory estimated by image guidance, with its proximal end guided and held in place by stereoguidance or robotic guidance during use. Alternatively, the guide tube 4 may be a severable guide tube that is cut to a predetermined length, with its distal end inserted into a predetermined position in the brain by image guidance, and its proximal end fixed within the skull during use. These embodiments will be described in detail below.

[0110] The guide tube 4 may have a proximal end configured to be guided and / or held by a stereotactic guide or robotic guide while the guide tube 4 is inserted into the brain and / or while the injectable fluid is delivered to the brain using the guide tube 4. The guide tube 4 may also have an adjustable clamp 92 used to hold the guide tube 4 at the correct insertion depth within the stereotactic guide. The clamp 92 is adjustable, allowing the guide tube 4 to be set to various insertion depths depending on the target region in the brain and the configuration of the particular stereotactic guide being used.

[0111] As shown in Figure 5, the diameter of the proximal end 28 of the guide tube 4 may be larger than the diameter of the distal end 18 of the guide tube 4. The diameter of the proximal end 28 of the guide tube 4 is a maximum of 7 mm, preferably a maximum of 6 mm, and more preferably a maximum of 5 mm. Because the proximal end 28 is large in diameter, the guide tube can be held or positioned more securely with stereotactic or robotic guidance. In this case, the large-diameter proximal end 28 is not inserted into the brain during use. During use, only the small-diameter distal end 18 is inserted into the brain.

[0112] The guide tube 4 can be held in a stereotactic or robotic guide using an insertion guide 1000 as shown in Figure 4. The insertion guide 1000 has an outer diameter suitable for holding in a stereotactic or robotic guide. The insertion guide is provided with a through-hole 1004 having a diameter approximately equal to the outer diameter of the proximal end 28 of the guide tube 4. The diameter of the through-hole 1004 should be slightly larger than the diameter of the proximal end 28 of the guide tube 4 so that the guide tube 4 can be easily inserted into the insertion guide 1000 and move up and down, but it does not need to be large enough to allow the guide tube 4 to move significantly laterally within the insertion guide 1000. The insertion guide 1000 may be provided with a clamp 1010 for holding the guide tube 4 in place after it has been fully inserted. The clamp 1010 prevents the guide tube 4 from moving while fluid is being delivered into the brain. The insertion guide 1000 has a narrower distal end 1006, and the diameter of the through-hole at the distal end 1006 may be approximately equal to the diameter of the distal end 18 of the guide tube 4.

[0113] The guide tube 4 shown in Figure 4 is a rigid guide tube. The guide tubes 4 in Figures 4 and 5 are made of rigid materials, such as ceramic, metals such as titanium or stainless steel, or rigid plastic materials such as PEEK. When the guide tube 4 is rigid, there is no need to pre-form a pathway in the brain, nor is there a need to support the guide tube 4 with a delivery probe when inserting it into the brain; it can be inserted directly into the brain. Rigid guide tubes 4 are particularly suitable for acute treatments, where the guide tube 4 is inserted into the brain to perform a specific procedure and then removed when the procedure is complete. This type of guide tube 4 is usually used with a stereotactic guide or robotic guide. The length of the rigid guide tube is 50 mm to 300 mm, preferably 100 mm to 250 mm. This allows it to extend from a location held by the stereotactic guide or robotic guide to a target volume in the brain.

[0114] When using a rigid guide tube 4, the fluid transfer tube 6 can be inserted into the through-hole 30 of the guide tube 4 before inserting the guide tube 4 into the brain, allowing the guide tube 4 and fluid transfer tube 6 to be inserted into the brain as a single unit. In this case, before inserting the cannula assembly into the brain tissue, the fluid transfer tube 6 is filled with fluid. This traps air within the fluid transfer tube 6, preventing it from being pushed into the brain when the fluid flows into the fluid transfer tube 6. The fluid transfer tube 6 is positioned and held within the through-hole 30 by a releaseable compression seal 42 located at the proximal end of the guide tube 4. If a depth control stopper 40 is present on the fluid transfer tube 6, the compression seal may interact with it. The fluid transfer tube 6 may be rigid. For example, the fluid transfer tube 6 may be made of or formed from a rigid material such as fused silica, a metal such as titanium or stainless steel, or a hard biocompatible plastic such as polyetheretherketone (PEEK).

[0115] The fluid transfer tube 6 can be positioned such that, when inserted into the through-hole 30 of the guide tube 4 before insertion into the brain, its distal end 10 is at least aligned with the distal end 18 of the guide tube 4, or protrudes beyond the distal end 18. Since the guide tube 4 is inserted into the brain tissue with the fluid transfer tube 6 protruding by a predetermined length from its distal end, when the distal end 18 of the guide tube 4 reaches the target region, the distal end 10 of the fluid transfer tube 6 also reaches the intended target. Alternatively, after inserting the guide tube 4, the distal end 10 of the fluid transfer tube 6 can be advanced through the tissue to a selected target.

[0116] Figures 7–15 show alternative designs for the guide tubes in Figures 4 and 5, in which the guide tube 4 is fixed to the skull after insertion and while the injector is being delivered using the guide tube 4. In contrast to the embodiment in which the guide tube is held by a stereoguide during injector delivery, allowing only one targeted injection at a time, the embodiment with bone fixation allows for simultaneous injections through multiple implantable devices. This significantly reduces procedure time and patient risk. This type of guide tube 4 can also be left in place for extended periods for use in cases requiring chronic or chronic intermittent injections.

[0117] The material and / or thickness of the guide tube 4 may be such that it can be cut by hand using a knife or sharp blade. Before insertion, the guide tube 4 may be cut to the desired insertion length for fixing its proximal end 28 to the skull. The guide tube 4 may be cut with a sharp blade using a cutting jig. The guide tube 4 may be cut together with the implantable plastic stylet inserted into the through-hole 30 of the guide tube 4. This stylet is cut together with the guide tube 4 and supports the guide tube 4 during the cutting process. Preferably, the guide tube 4 is cut in the same cross-section as one of the decompression regions 72, especially when the decompression region is formed by a circumferential groove. This provides the distal end 18 of the guide tube 4 with a relatively rounded profile, which reduces tissue trauma during insertion compared to cutting perpendicularly through the maximum diameter of the guide tube 4.

[0118] The length of the guide tube that can be cut is 25 mm to 150 mm. Preferably, the maximum length of the guide tube that can be cut is 110 mm. For example, the length may be between 50 mm and 110 mm. This allows the guide tube to reach a typical target volume in the human brain, for example, if the proximal end of the guide tube is fixed to the skull.

[0119] Figure 7 shows a cross-section of an example of this type of guide tube 4. The guide tube 4 in Figure 4 comprises a proximal end 28, a distal end 18, and a through-hole 30 through which a fluid transfer tube 6 (such as a cannula) passes. The guide tube 4 has a sealing region 70 which includes one or more depressurization regions 72 in the form of a circumferential groove arranged along its outer diameter.

[0120] When in use, the guide tube 4 has a proximal end 28, which does not enter the brain but is fixed to or near the patient's skull, thereby fixing the position of the guide tube 4 within the brain. Similar to conventional arrangements, the guide tube 4 of the present invention may have an enlarged portion at the proximal end 28 that is sized and shaped to be fixed into a trepanation hole in the skull. The enlarged portion may include a large-diameter section 90. For example, the guide tube 4 may have an inner layer 26 superimposed on an outer layer 24, as shown in Figure 2 and further described below. The inner layer 26 has an overmolded large-diameter section 90 at its proximal end, which forms a flare or stopper to limit the insertion depth and facilitate fixation to the skull.

[0121] Advantageously, the guide tube 4 can be inserted through a trepanation hole in the skull from which the guide hub 50 is already attached, as shown in Figures 12 and 13. The guide hub 50 is for fixing the guide tube 4 to the patient's skull before insertion into the brain. Another guide hub 50 may be provided as part of a neurosurgical apparatus that includes the guide tube 4, optionally a fluid transfer tube 6, and / or other components described below. The guide hub 50 is provided with a passage 52 through which the guide tube 4 passes. The guide hub 50 provides a reference point for fixation in the skull from which the direction and length of the probe, guide tube 4, and fluid transfer tube can be controlled.

[0122] When a guide hub 50 is used, the guide tube 4 may have a large-diameter portion 90 as described above, which is open at its proximal end 28 for fixing within the guide hub 50 during use. The large-diameter portion 90 of the guide tube 4 may be configured to engage with the guide hub 50 by engaging with a correspondingly shaped seat in the guide hub passage 52, for example. The large-diameter portion 90 may be cylindrical, partially spherical, or conical ("flared"), for example.

[0123] The proximal end 28 of the guide tube 4 can be fixed to the guide hub 50 by a fitting, such as a threaded fitting 100 having a through hole. As shown in Figure 14, the threaded fitting 100 is screwed into the proximal face 102 of the large-diameter portion 90 of the guide tube 4, compressing the large-diameter portion 90 against a correspondingly shaped sheet 104 in the guide hub passage 52. The assembled neurosurgical apparatus is also shown in Figure 15.

[0124] Advantageously, by compressing the large-diameter portion 90 of the guide tube 4, a fluid seal can be formed between the guide tube 4 and the guide hub 50, and between the guide tube 4 and the threaded joint 100. By interposing a deformable washer, such as a silicone washer, between the distal end of the threaded joint 100 and the proximal surface 102 of the large-diameter portion 90 of the guide tube 4, the fluid transfer tube 6 can be compressed radially and sealed. This fixes the position of the fluid transfer tube 6 relative to the guide hub 50 and the skull. Such a washer can also compress the fluid transfer tube 6, thereby forming a fluid seal between the fluid transfer tube 6 and the guide tube 4.

[0125] If the fluid transfer tube 6 has a depth control stopper 40 at its proximal end, a fluid seal can be formed between the fluid transfer tube 6 and the guide tube 4. The depth control stopper 40 may be a threaded stopper that is screwed into a complementary thread in a hole in the guide hub 50. For example, the depth control stopper 40 may form a conical seal between the conical shape of the distal end of the depth control stopper 40 and the large-diameter portion 90 of the guide tube 4.

[0126] At least the outer layer 24 of the guide tube 4 may be elastically deformable, as described later. In this case, when the large-diameter portion 90 is inserted into the guide hub 50 and the distal surface of the depth control stopper 40 of the fluid transfer tube 6 is securely engaged with the large-diameter portion 90, the deformable outer layer 24 is compressed against the large-diameter portion 90, forming a fluid seal. This blocks a potential leakage route for fluid that could backflow from between the through-hole 30 of the guide tube 4 and the fluid transfer tube 6 to the outside of the central nervous system. This seal also blocks a potential entry route for bacteria into the brain.

[0127] The engagement of the large-diameter portion 90 of the guide tube 4 with the guide hub 50 allows for the formation of a fluid seal between the guide tube 4 and the guide hub 50. For example, this can be achieved by engaging the distal surface of the large-diameter portion 90 with a sheet of the corresponding shape in the guide hub passage 52. The force compressing the proximal surface 102 of the large-diameter portion 90 of the guide tube 4 is also transmitted to the distal surface of the large-diameter portion 90 that is in contact with the sheet of the corresponding shape in the guide hub 50. If the guide tube 4 has an elastically deformable outer layer 24, the engagement of the large-diameter portion 90 of the guide tube 4 with the guide hub 50 includes compression of the outer layer 24. Compressing the outer layer 24 with the distal surface of the large-diameter portion 90 forms a sealed fluid seal that prevents cerebrospinal fluid from leaking outside the skull.

[0128] As shown in Figures 7 and 9, the through-hole 30 of the guide tube 4 within the large-diameter section 90 may have a diameter that increases towards the proximal end of the large-diameter section 90. This allows the fluid transfer tube 6 to be guided into the through-hole 30, making assembly easier during use.

[0129] The large-diameter section 90 (also called the flared section) may include a non-compliant core 96 located inside the outer layer 24. The non-compliant core 96 forms the large-diameter section 90 of the guide tube 4. This is because other layers (such as the outer layer 26) are positioned on the non-compliant core at the proximal end 18. The non-compliant core 96 can be made of PEEK. Alternatively, the non-compliant core 96 can be integrally molded with the inner layer 26. Or, the non-compliant core 96 may be made of a different material from the rest of the guide tube 4. For example, the non-compliant core 96 may be formed by an overmolding process in which a different polymer is applied to the end of the guide tube 4.

[0130] The non-compliant core 96 may be overmolded onto the proximal end of the inner layer 26 and positioned outside the inner layer 26. In this case, the inner layer 24 does not have to extend to the proximal end of the large diameter section 90. The inner layer 24 may extend up to 80%, optionally up to 60%, of the large diameter section 90. This allows the non-compliant core 96 to define the through hole 30 at the proximal end of the guide tube 4.

[0131] The outer layer 24 may be electrospun onto the outer surface of the large-diameter portion 90. As described above, this large-diameter portion 90 is useful for fixing the guide tube 4 inside the skull and for forming a seal around the proximal end 28 of the guide tube 4.

[0132] The non-compliant core 96 can be configured to allow gas to pass through it. For example, the non-compliant core 96 may be molded with through-holes or passages, or it may be formed from a gas-porous material such as a sintered polymer. This allows the non-compliant core to contribute to the gas venting function of the guide tube 4 (described later). In this case, increasing the diameter of the through-hole 30 toward the nearest end of the guide tube 4 increases the exposed surface area of ​​the non-compliant core 96, further increasing the contribution of the non-compliant core 96 to the gas venting function.

[0133] The use of a porous non-compliant core 96 is also advantageous in simplifying manufacturing. If the non-compliant core 96 is not porous, the gas can only be vented through the porous layer, and for this to be effective, the proximal surface of the large-diameter section 90 of the guide tube 4 must be exposed to the atmosphere. Ensuring that this surface is exposed requires additional manufacturing steps, such as masking the proximal surface of the guide tube 4 when forming other layers. By using a porous non-compliant core 96, the gas can be vented through the non-compliant core 96 and the proximal end of the through-hole 30, so a porous layer can be formed on the non-compliant core 96 without the need to shield the proximal surface of the large-diameter section 90 of the guide tube 4. As a result, the number of manufacturing steps for the guide tube 4 is reduced, significantly speeding up the manufacturing process, reducing handling, and lowering costs.

[0134] Convection-enhanced delivery techniques can be used for both acute (short-term) and chronic (long-term or repeated) delivery of treatments to brain tissue. For example, gene therapy may be administered in a single treatment session, while other treatments, such as chemotherapy, may require repeated infusions into the brain (chronic treatment plans).

[0135] In any case, especially when a long-term or chronic treatment plan is employed, it is highly desirable to keep the distal end 18 of the guide tube 4 in place within the brain tissue. The distal end 18 of the guide tube 4 is typically positioned at the proximal end of the cannula's trajectory. The cannula's trajectory constitutes the final distal section of the trajectory to the target in the brain, traversing the target region around the target. The distal end 18 of the guide tube 4 plays a role in retaining the injectable fluid in the target region by resisting backflow at the step 20 formed between the respective diameters of the guide tube 4 and the fluid transfer tube 6, as described above.

[0136] Fixing the proximal end 28 of the guide tube 4 to the skull (or to a guide hub 50 fixed to the skull) provides a relatively safe placement for long-term or chronic treatment. However, the brain is mobile relative to the skull. Therefore, when the brain moves during use, the guide tube 4 may be subjected to axial and even lateral forces. Such forces can cause repeated damage to brain tissue by the distal end 18 of the guide tube 4. This can lead to tissue vacuolation and the formation of low-resistance pathways at the step 20, which increase rather than resist backflow and may result in a loss of therapeutic effect from the target. A flexible guide tube 4 can mitigate this problem by allowing the distal end 18 of the guide tube 4 to move relative to the proximal end 28 fixed to the skull.

[0137] At least the proximal portion 38 of the guide tube 4 may be elastically deformable along the axial direction of the guide tube 4. Elastic deformation may include axial extension and / or compression. At least the proximal portion 38 may be composed of a material whose Poisson's ratio is close to zero or negative when deformed axially (e.g., extension or compression), i.e., a material whose wall thickness does not substantially change during deformation (under small strains). For example, stretched polytetrafluoroethylene (ePTFE) or polyurethane foam can exhibit this property. More generally, many polymer foams have a Poisson's ratio of nearly zero because air tends to escape when compressed.

[0138] The proximal portion 38 may be located outside the brain during use (but may be within the skull and / or cranial cavity). The proximal portion 38 may extend from outside the brain to the nearest end of the guide tube 4, or in the direction in which the nearest end of the guide tube 4 is located. At least the proximal portion 38 of the elastically deformable guide tube 4 can expand and contract in response to changes in the distance between the brain and the fixed proximal end 28 of the guide tube 4 located in the skull. The elastically deformable proximal portion 38 can be provided in any suitable manner. For example, the entire guide tube 4 may be elastically deformable.

[0139] Optionally, as shown in Figures 2, 7, and 9, the guide tube 4 is a laminated structure including, for example, at least an inner layer 26 and an outer layer 24, wherein the rigidity of the inner layer 26 may be greater than that of the outer layer 24. The outer layer 24 is elastically deformable, and the inner layer 26 may be configured to include a spring 76 at the proximal portion 38 of the guide tube 4. Figure 7 shows a cross-section of the guide tube 4 having an inner layer 26 and an outer layer 24. In Figure 8, the inner layer 26 is shown separately from the outer layer 24. The proximal portion of the rigid inner layer 26 immediately distal to the proximal end 28 of the guide tube 4 may be in the shape of a spring 76 formed, for example, by making a helical notch along its long axis in the wall of the inner layer 26. The length of the spring 76 is between 5 mm and 30 mm, preferably between 10 mm and 20 mm. With the proximal end 28 of the guide tube 4 fixed to the skull, the spring 76 of the inner layer 26 of the guide tube 4 can adapt to the movement of the brain relative to the fixation of the skull, while the distal end 18 of the guide tube 4 remains fixed in its position within the brain tissue.

[0140] The outer layer 24 of the guide tube 4 is made of an elastically deformable material that can accommodate a desired range of movement on the proximal portion 38. For example, the outer layer 24 may be made of electrospun, low-durometer polyurethane or PTFE. When formed by electrospun, the outer layer 24 may have a higher proportion of transversely oriented fibers to increase axial compliance. The compliance of the guide tube 4 at the proximal portion 38 can be increased by reducing or eliminating adhesion of the outer layer 24 to the spring portion of the inner layer 26 of the guide tube 4. For example, electrospun polyurethane has poor adhesion to a smooth PEEK surface, but this can be overcome by immersing the PEEK in a polyurethane solution, laser etching the surface, polishing the surface, or plasma treating the surface. If the inner layer 26 is made of PEEK and is immersed in a polyurethane solution, laser etched, polished, or plasma treated except for the spring portion, the outer layer 24 will have little to no adhesion to the spring 76 of the inner layer 26.

[0141] When the guide tube 4, equipped with a spring-like proximal portion 38 (as described below), is delivered into the brain parenchyma using a delivery probe, the coaxial force applied to the guide tube 4 compresses the spring 76, making the strength of the guide tube column sufficient to deliver the guide tube to the desired target. In its original position, when the delivery probe is removed and replaced with a fluid transport tube 6, the distal end 18 of the guide tube 4 remains fixed in its position within the brain, even if the fluid transport tube 6 moves relative to the guide tube 4. The relative movement of the fluid transport tube 6 and the guide tube 4 may increase backflow along the fluid transport tube 6. However, this is limited to the target volume because the step 20 formed by the distal end of the guide tube 4 and the seal region 70 of the guide tube 4 (i.e., the primary control of backflow) resides in the fixed position of the target in the brain. The seal region 70 also helps to hold the distal end 18 of the guide tube 4 in its target position, as the decompression region 72 acts to push into the brain tissue.

[0142] Instead of providing the inner layer 26 with a spring portion as shown in Figures 7 and 8, the inner layer 26 may be reduced or eliminated in the proximal portion 38. The guide tube 4 comprises at least an inner layer 26 and an outer layer 24, the inner layer 26 being more rigid than the outer layer 26, and the outer layer 26 being elastically deformable as in the conventional design.

[0143] The inner layer 26 extends proximally from the distal end 18 of the guide tube 4, but not to the nearest end of the guide tube. Rather, the inner layer 26 does not extend into the proximal portion 38 of the guide tube 4. As a result, the proximal portion 38 of the guide tube extends from the nearest end of the guide tube 4 to the starting point of the inner layer 26, excluding the inner layer 26. The proximal portion 38 can be sized to extend from the patient's skull to the outer layer of the brain, or toward the outer layer of the brain, during use. Because the relatively rigid inner layer 26 is not present in the proximal portion 38, the proximal portion 38 can stretch and contract, thereby allowing the distal end of the guide tube to remain in a predetermined position within the brain tissue.

[0144] If the guide tube 4 is flexible, the fluid transfer tube 6 may also be flexible. For example, the fluid transfer tube 6 may contain a flexible material or be made from a flexible material. This allows the fluid transfer tube 6 to move and maintain its intended position at the target, especially when the brain moves relative to the skull during lateral brain movement.

[0145] The guide tube 4 may be composed of heterogeneous materials and / or multiple materials having different properties. This mainly applies to guide tubes 4 fixed to the skull, as shown in Figures 7-15. Guide tubes 4, such as the one shown in Figure 5, may have multiple layers, but are mostly formed from a single homogeneous layer.

[0146] For example, as described above, the guide tube 4 may have a laminated structure. This allows for a desirable combination of features, including, as will be described later, an overmolded structure that forms a flared or enlarged proximal end, the ability to expel air along the length of the guide tube 4, and a finely grooved guide tube 4 with sufficient axial rigidity to maintain structural integrity when delivered into the tissue.

[0147] In some situations, such as when using a rigid guide tube 4 as shown in Figure 5, the fluid transfer tube 6 and guide tube 4 can be assembled together and delivered into the brain together. In other situations, such as when using a guide tube 4 fixed to the skull as shown in Figures 7-15, the distal end 10 of the fluid transfer tube 4 is passed through the through-hole 30 of the guide tube 4 after the guide tube 4 is inserted into the brain, passes through the proximal end 28 of the guide tube 4 to the distal end 18, and is delivered to the target in the brain parenchyma. While the fluid transfer tube 6 passes through the through-hole 30 of the guide tube 4, the column of air inside the guide tube 4 is pushed distally in a piston-like motion. This can potentially tear the brain tissue in the target area.

[0148] To mitigate this, the guide tube 4 may be configured to discharge gas from the through-hole 30 to the proximal end 28 of the guide tube 4, preferably through the inner surface of the through-hole 30.

[0149] The guide tube 4 may have a porous layer that allows air to pass through, and the porous layer may contain a hydrophobic material. The porous layer may be the outermost layer of the guide tube 4. To maintain the air porosity of the guide tube 4, the porous layer is in gas communication with the through-holes 30. The porous layer forces air into the walls of the guide tube 4, and rather than being forced into the brain parenchyma of the target region, it is expelled into the atmosphere from its proximal end 28. This helps to avoid damage to brain tissue. When the fluid transfer tube 6 is fully inserted into the guide tube 4, the expulsion of air from the guide tube 4 into the atmosphere may be stopped. At this point, the distal surface of the depth control stopper 40 on the fluid transfer tube 6, or an intervening washer, may engage with the proximal surface of the proximal end of the guide tube 4 to form a seal.

[0150] The porous layer may contain hydrophobic or superhydrophobic materials. Hydrophobic means that the static contact angle θ at the liquid-vapor interface of water droplets on the material surface is greater than 90°. For superhydrophobic materials, the static contact angle is θ > 150°. Instead of using a porous layer composed entirely of hydrophobic material, the porous layer may have an inner permeable layer that is neither hydrophobic nor superhydrophobic. The inner permeable layer is sealed by a liquid-impermeable layer to prevent liquid from entering through the outer diameter of the guide tube 4. The liquid-impermeable layer may be made from a hydrophobic or superhydrophobic material.

[0151] A further advantage of using a porous layer at least on the outermost layer of the guide tube 4 is that the brain tissue can penetrate the porous structure, allowing for integration with the brain tissue over time. This helps to fix the guide tube 4 in the desired position even if the compressive force between the brain tissue and the guide tube 4 decreases over time. By integrating the guide tube 4 with the brain tissue, a clearly defined interface between the guide tube and the tissue can be eliminated, thereby further reducing the possibility of backflow.

[0152] Alternatively, the guide tube 4 may be provided with a liquid-impermeable coating layer, which may offer advantages such as reduced trauma during insertion and improved sealing. Preferably, the coating layer is lubricating to reduce trauma during insertion as described above. The coating layer may be provided on a porous layer. Preferably, the coating layer is not provided on at least a portion of the proximal surface of the guide tube 4 so as not to obstruct the discharge of air from the porous layer at the proximal end of the guide tube 4 to the atmosphere during use.

[0153] Suitable constituent materials for at least the porous layer of the guide tube 4 include at least one of sintered polytetrafluoroethylene (PTFE), sintered polyurethane, stretched PTFE, silicone foam, polyurethane foam, shape memory polymer, microporous hollow extruded polymer fiber, or electrospun polymer. Microporous hollow extruded polymer fiber and / or electrospun polymer may include at least one of polytetrafluoroethylene, polyvinylidene fluoride, polyurethane, polypropylene, and copolymers thereof. Shape memory polymers can be used. Electrospun polyurethane is air-porous and can be manufactured in hydrophobic, superhydrophobic, or non-hydrophobic forms. When foam is used, at least some of the foam cells are open cells to allow air to pass through the bulk material. All or almost all of the foam structure outer layer 24 or porous layer of the guide tube 4 may be open-cell foam.

[0154] As described above, it may be necessary to cut the guide tube 4 to a desired length before implanting it in the brain. If the outer layer 24 is elastically deformable, cutting the guide tube 4 can be more difficult because the outer layer 24 of the guide tube 4 tends to deform when a cutting force is applied. To solve this problem, the guide tube 4 can also be provided as part of a package. The package comprises the guide tube 4 and a packaging tube, with the guide tube 4 housed inside the packaging tube. The packaging tube may have higher rigidity than the outer layer 24 of the guide tube 4. The packaging tube holds the guide tube 4 in place, reduces the tendency of the guide tube 4 to deform when a cutting force is applied, and ensures that the distal end 18 of the guide tube 4 can be cleanly cut axially. Once the guide tube 4 has been cut to the appropriate length, it can be removed from the package immediately before insertion into the brain. The packaging tube also reduces direct handling of the outer surface of the guide tube 4 before implantation, thereby reducing the possibility of contamination of the guide tube 4 by, for example, pathogens. As described above, the package may further include a stylet within the through-hole 30 of the guide tube 4. The stylet further reduces the deformation of the guide tube 4 during cutting.

[0155] If the guide tube 4 is composed of heterogeneous materials and / or multiple materials having different properties, the stiffness may vary in particular, and the guide tube, especially the porous layer, may include heterogeneous materials and / or multiple materials having different stiffnesses. For example, the stiffness of the porous layer may be greater at or near the through-hole 30. The porous layer may consist of an electrospun polymer or foam whose density increases radially inward from the outside toward the through-hole 30, or a region where the density is increased at or near the through-hole 30. The increased density increases the stiffness and provides support to the more porous and flexible outer region.

[0156] As shown in the examples in Figures 9 and 10, the reinforcement may be applied along the entire length or nearly the entire length of the guide tube. However, in some embodiments of the present invention, the method of reinforcement may vary along the length of the guide tube 4. For example, as described above, it is not necessary to reduce the stiffness of the proximal end 28 of the guide tube 4 or to provide additional stiffness in order to allow axial deformation of the guide tube 4.

[0157] Alternatively or additionally, as shown in Figures 7-10, the guide tube 4 may have a laminated structure with a more rigid inner layer 26 (or more layers) in or near the through hole 30. In this case, the porous layer comprises at least an inner layer 26 and an outer layer 24, with the rigidity of the inner layer 26 being higher than that of the outer layer 24. For example, the more rigid inner layer 26 may be formed on the surface of the through hole 30. The inner layer 26 is the innermost layer of the guide tube 4 and forms the surface of the through hole 30. The rigider inner layer 26 supports the more flexible outer layer 24. The porous outer layer 24 may be electrospun, for example, on a relatively rigid inner layer 26 formed by electrospun or microperforated PEEK tubing.

[0158] The harder inner layer 26 is made of a hydrophobic or superhydrophobic material to prevent liquid penetration through the guide tube structure. However, this is not mandatory, and one or more layers may not be hydrophobic or superhydrophobic.

[0159] The inner layer 26 may include polymer materials comprising, for example, at least one of fluoropolymers such as polyetheretherketone, nylon, polyurethane, polyester, and polytetrafluoroethylene; polymer perfluoroethers such as perfluoroalkoxyalkanes, polyvinylidene difluoride, or fluorinated ethylene propylene; liquid crystal polymers; and mixtures or copolymers thereof. The inner layer 26 can be manufactured by a process comprising at least one of sintering, extrusion with microparticle leaching, micro-perforation of a tube by drilling or laser, weaving, knitting, or electrospinning polymer fibers around a cylindrical mold to form a tube of porous polymer sheet material, and 3D printing a polymer in a porous form.

[0160] To maintain the porosity of the guide tube 4, it is preferable that the porous outer layer 24 is in gas communication with the through-hole 30 over a substantial portion of the length of the guide tube 4, for example, at least 25%, and optionally at least 50%. If the guide tube has a multilayer or laminated structure, a more rigid inner layer 26 (or more layers) located in or near the through-hole 30 can be configured to allow air to pass through the inner layer 26. This allows air in the through-hole 30 to be expelled through the porous material of the outer layer 24 of the guide tube 4. However, if the inner layer 26 is not configured to allow air to pass through, the air pushed out through the through-hole 30 may be removed from the distal end 18 of the guide tube 4 upon contact with the most distal end of the porous outer layer 24 and return through the porous outer layer 24 to the proximal end 28 of the guide tube 4.

[0161] The inner layer 26 may be made of a material that is permeable to air. Alternatively, the inner layer may be made of a material that is inherently non-porous, but can be manufactured in various ways to allow air to pass through. For example, as shown in Figures 6 to 10, the inner layer 26 may have a number of holes 78 that penetrate through it. The holes 78 may be provided over at least 25%, optionally at least 50%, and optionally at least 75% of the length of the inner layer 26. The holes 78 can be formed by micro-perforating the material used to form the inner layer 26, by drilling holes, or by using a laser. The porous inner layer 26 can also be formed by weaving, knitting, or electrospinning polymer fibers around a cylindrical mold to form a tube of porous polymer sheet material. 3D printing can also be used to manufacture the porous inner layer 26.

[0162] The inner layer 26 may, as described above, include a proximal overmolded large-diameter portion 90 made of, for example, PEEK, which is also called a flared portion. The large-diameter portion 90 may be made of a different material from the rest of the guide tube 4. For example, the large-diameter portion 90 may be formed by an overmolding process in which a different polymer is applied to the end of the guide tube 4. The air-porous outer layer 24 may be formed by electrospinning on the outer surface of the large-diameter portion 90, for example, as shown in Figure 11. This large-diameter portion 90 serves to secure the guide tube 4 within the skull and / or to form a seal around the proximal end 28 of the guide tube 4, as will be further described below.

[0163] Manufacturing the guide tube 4 by electrospinning offers the advantage of precisely controlling not only the device's shape but also its mechanical and chemical properties. For example, by collecting fibers on a rotating metal rod, rigid, air-porous, thin tubes can be electrospun from polymers such as PEEK and LCP. By adjusting the rotation speed of the rod collector and using shaping electrodes, guide electrodes, and shield electrodes, the fibers can be layered along both the longitudinal and transverse axes, controlling porosity and maximizing the strength of the column.

[0164] The outer layer 24 of the guide tube 4 may be electrospun on a harder inner layer 26 with a polymer having desirable properties such as hydrophobicity, superhydrophobicity, tissue adhesion, and better compliance.

[0165] The reduced-pressure region 62 can be formed by a process of sintering, molding, or electrospinning the porous layer 24. For example, the reduced-pressure region 72 can be formed by creating multiple circumferential rings with fibers aligned circumferentially along the long axis of the guide tube 4. This can be achieved, for example, by electrospinning on a rotating metal rod with circumferential grooves or insulating rings along its length to create high-current-density sections where fibers are deposited to the maximum extent, and / or by arranging focusing electrodes, steering electrodes, and guide electrodes in combination with a tightly controlled rotational speed of the rod.

[0166] The reduced-pressure region 72 can also be formed by creating a guide tube 4 with a uniform diameter, and then using one or more heated rollers to process the guide tube 4 to form a seal region 70. The heated rollers have circumferential projections with widths and spacings that match the desired configuration of the reduced-pressure region 72, and their axis of rotation is parallel to the axis of the guide tube. The rollers are simultaneously pressed against the outside of the guide tube 4, and the diameter of the guide tube 4 can be reduced in the reduced-pressure region 72. The heated rollers and / or the guide tube 4 may rotate during this process. If the guide tube 4 (or at least its outer layer 24) is formed by electrospinning, the heated rollers act to compress and fuse the fibers of the outer layer 24, thereby potentially reducing the diameter of the guide tube 4 in that region.

[0167] It is also possible to use three parallel axes of heating rollers, place a guide tube between them, and apply the rollers from three sides of the parallel guide tube. Then, rotate the rollers in the same direction (clockwise or counterclockwise) and rotate the guide tube around its longitudinal axis to create a single groove or a series of grooves around the entire circumference of the guide tube.

[0168] The reduced pressure region 72 may be provided by a coating layer as described above. For example, the coating layer may include a non-porous, lubricated heat-shrinkable tube that is applied on an elastically deformable porous layer and shrinks locally along its axis when rolled between heating rollers having transversely parallel ridges on its surface. For example, the reduced pressure region 72 can be formed by sliding a heat-shrinkable polymer tube on the outer surface of the electrospinning guide tube and then positioning the structure between parallel heating rollers as described above. The rollers apply various heats and compressions to the outer surface of the heat-shrinkable tube, forming a series of grooves on the outer surface of the guide tube. Fluorinated ethylene propylene (FEP), polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), or polyolefins can be used as the heat-shrinkable material. Alternatively, a heat-shrinkable polymer tube with annular thickness spaced apart along the wall may be directly attached to the outer surface of the electrospinning guide tube, uniformly heated and shrunk, and mechanically fixed to the guide tube. The molded outer surface of the heat-shrinkable tubing not only provides a reduced pressure area, but can also provide the guide tube with a lubricated and liquid-impermeable outer surface.

[0169] Rigid, air-porous guide tubes can be formed by sintering hydrophobic thermoplastic polymers, such as polytetrafluoroethylene (PTFE), polyethylene (PE), polypropylene (PP), high-density polyethylene (HDPE), ultra-high molecular weight polyethylene (UHMWPE), and polyvinyl chloride (PVDF). The sintered mold may contain core pins that are tensioned to maintain linearity, or core pins made from very hard materials such as tungsten carbide. The inner surface of the sintered mold is provided with circumferential grooves, thereby forming a guide tube with a reduced-pressure region on its outer surface. A lubricating and liquid-impermeable surface can also be formed by thermally shrinking a thermoplastic polymer tube on the outer surface of the sintered guide tube. Alternatively, a molded guide tube with a reduced-pressure region can be created by thermally shrinking a thermoplastic polymer tube, which has annular thickness spaced along the wall, onto the outer surface of a sintered polymer guide tube with a uniform diameter.

[0170] It is important to prevent air from being delivered into the brain through the fluid transfer tube 6, and to mitigate this risk, a bubble vent 74 may be provided on the fluid transfer tube 6. The bubble vent 74 is preferably located at the proximal end of the fluid transfer tube 6, as shown in Figure 16. The configuration and components of the bubble vent 74 are described below and shown in Figure 16. The bubble vent 74 is configured to prevent gas from entering the fluid transfer tube 6. The bubble vent 74 reduces the risk of air bubbles entering the brain when air bubbles emerge from or mix with the infusion solution during connection and / or disconnection of a delivery system used to deliver the infusion fluid to the fluid transfer tube 6, such as a dispenser, infusion line, and / or pump. Air bubbles injected into brain tissue can tear the tissue and disrupt the distribution of the therapeutic fluid / infusion fluid. Because the bubble vent 74 is permanently connected to and / or integrally formed with the fluid transfer tube 6, the possibility of air bubbles entering while the fluid transfer tube is connected to a delivery system is further reduced. The bubble vent 74 is preferably provided integrally with the cannula 6, as shown in Figure 16. Additionally or alternatively, the bubble vent 74 may be configured to prevent pathogens (e.g., microorganisms such as bacteria) from entering the fluid transfer tube 6. This reduces the risk of intracranial infection occurring as a result of the treatment.

[0171] Figure 17 shows an exploded view of a bubble vent 74 configured to be attached to a cannula 6 and a fluid connector of the delivery system. The bubble vent 74 includes a perforated filter guard 80, a bubble filter 82, retaining rings 83A, 83B, a retaining cap 84, a partition stopper 86, and a partition cap 88. The bubble vent 74 may also include a low-volume bubble filter 82 made, for example, from stretched polytetrafluoroethylene (ePTFE). The bubble filter 82 may have a hydrophobic (optionally superhydrophobic), gas-permeable, microporous structure configured to remove bubbles from the flowing therapeutic / infusion fluid. The bubble filter 82 may be effective in removing bubbles when the flow rate is 30 μl / min or less. The bubble vent 74 may further include a filter guard 80. In the illustrated example, the bubble filter 82 is effective in removing bubbles when the flow rate is 30 μl / min or less. The filter 82 is housed within a perforated filter guard 80. In the illustrated example, the bubble filter 82 is housed on a hollow post 85 and is held in place by a retaining ring 83A positioned concentrically with the filter guard 80.

[0172] The filter guard 80 consists of a hollow shell with multiple perforations 87 (small holes) distributed around the shell wall, which facilitates the degassing of the fluid / injection liquid as it flows through the bubble vent 74 into the fluid transfer tube 6. The filter guard 80 can also protect the bubble filter 82 from damage. The combination of the bubble filter 82 and the filter guard 80 allows for the easy dispersal of air and bubbles contained in the fluid flow before the fluid enters the fluid transfer tube 6.

[0173] The bubble vent 74 is equipped with a retaining cap 84, which connects to the filter guard 80 to complete the assembly of the bubble vent 74 and house the bubble filter 82 within the bubble vent 74. The retaining cap 84 includes a hollow retaining post 89 and a retaining ring 83B that engages with the bubble filter 82, thereby ensuring that the bubble filter 82 is properly positioned and held within the filter guard 80 and that the bubble filter 82 functions efficiently during use. The retaining cap 84 also includes a partition stopper 86, which provides a sealed unit until the partition 86 is punctured by a hollow needle to provide a fluid connection with the fluid transfer tube 6. The partition stopper 86 may be compressed and held by a partition cap 88. The retaining cap 84 and the filter guard 80 may be joined by a snap-fit ​​connection. However, alternative arrangements such as screw connections, welded connections, or adhesive connections may also be used to join them.

[0174] The bubble vent 74, incorporating a bubble filter 82, reduces the risk of air being delivered to the brain or other organs along with the fluid containing the therapeutic agent / injection. It is understood that fluid containing air / bubbles can occupy space, potentially stretching or tearing brain tissue, and may also interfere with the delivery / distribution of the therapeutic agent / injection. The bubble vent 74 also serves to filter pathogens such as bacteria and other microorganisms from the fluid.

[0175] Figures 18-21 show alternative designs for the bubble vent 174. Figure 18 shows the bubble vent 174 in an assembled state for use. Similar to the bubble vent 74, the bubble vent 174 includes a retaining cap 84. The retaining cap 84 includes a proximal connector 176, such as a screw connector, which connects to the fluid connector of the delivery system.

[0176] Figure 19 shows an exploded view of the bubble vent 174, and Figure 20 shows a cross-sectional view. The proximal connector 176 may include a partition wall 86. This allows the proximal connector 176 to be sealed until the partition wall 86 is punctured, for example, by a hollow needle. The bubble vent 174 includes a fluid passage 140 that fluidly connects the proximal connector 176 to the fluid transfer tube 6. In this design, the bubble vent includes a first membrane 150 and a second membrane 152. The first membrane 150 and the second membrane 152 are positioned between the distal end of the fluid passage 140 and the proximal end of the fluid transfer tube 6. The first membrane 150 and the second membrane 152 may be substantially parallel to each other or substantially perpendicular to the axis of the fluid passage 140. Since the first membrane 150 is positioned closer to the distal end of the fluid passage 140 than the second membrane 152, the fluid entering the bubble vent 174 through the partition wall 86 reaches the first membrane 150 before the second membrane 152. An annular washer 153 can be placed between the first membrane 150 and the second membrane 152, thereby forming a peripheral fluid seal between the membranes and the housing of the connector 174, separating the membranes in the center and forming a cylindrical gap between them. The diameter of the cylindrical gap ranges from 2 mm to 6 mm, but is most preferably 4 mm. This gap can separate the membranes 150 and 152 by 0.05 mm to 0.2 mm, but is most preferably 0.1 mm. The first membrane 150 and the second membrane 152 may be connected to each other and to other components of the bubble vent 174 via a connecting surface 180. The connecting surface 180 can be connected by any suitable method, such as ultrasonic welding or using an adhesive layer. The bubble vent 174 may also include a support member 184 that supports the distal surface of the second membrane 152, allowing the fluid that has passed through the second membrane 152 to easily reach the cannula 70.

[0177] The first membrane 150 is hydrophobic and gas permeable. A hole 154 is provided in the first membrane 150, where the fluid passage 140 is in contact with the first membrane 150. This allows fluid from the fluid passage 140 to pass through the first membrane 150 via the hole 154. The partition sealing connector 174 may include a support member that supports the proximal surface of the first membrane 150, and an annular connecting surface to which the membrane is attached around the support member and around the central hole 154 (not shown in Figure 19). The second membrane 152 is liquid permeable and preferably hydrophilic. The second membrane 152 does not need to be hydrophilic, but using a combination of hydrophobic and hydrophilic membranes provides the most efficient venting. If only the hydrophobic first membrane 150 is used, atmospheric air may pass through the first membrane 150 and be drawn into the injection fluid if the pressure in the line falls below atmospheric pressure. This can occur if the connector is elevated more than 10-25 cm above the skull (depending on intracranial pressure). Because the second membrane 152 is hydrophilic, it can prevent air from entering the brain even in such a situation. The second membrane 152 is impermeable to gases and bacteria. Since the second membrane 152 has no holes, the fluid from the fluid passage 140 must pass through the material of the second membrane 152 in order to reach the fluid transfer tube 6. The bubble vent 174 on the proximal side of the first membrane 150 is provided with one or more vents 160 (for example, two vents in the example in Figure 9). Where the vents 160 are in contact with the first membrane 150, the first membrane 150 has no holes, so the fluid from the fluid passage 140 must pass through the material of the first membrane 150 in order to reach the vents 160.

[0178] The operation of the bubble vent 174 is shown in an enlarged view in Figure 21. A mixture of liquid and gas (e.g., the infusion fluid delivered to the patient's brain via the fluid transfer tube 6, and the air bubbles mixed with it) enters the bubble vent 174 through the partition 86 and the fluid passage 140. This mixture passes through the first membrane 150 via the hole 154. The liquid is drawn into the hydrophilic second membrane 152 and permeates through the (liquid-permeable) second membrane 152 to flow into the cannula. The layer of liquid and the second membrane 152 form a barrier that prevents gas from entering the fluid transfer tube 6. The gas can pass through the air gap between the first membrane 150 and the second membrane 152, through the gas-permeable first membrane 150, and escape from one position of the vent hole 160. The hydrophobicity of the first membrane 150 repels the liquid, preventing it from forming a barrier similar to that of the second membrane 152, thereby allowing the gas to be discharged through the vent 160 and out of the bubble vent 174.

[0179] A neurosurgical device including a guide tube 4 may further include a probe 60 configured to be inserted into brain tissue, as shown in Figure 22. The probe may be a pathway-forming probe. The probe 60 is passed through brain tissue before insertion of the guide tube 6 to form a pathway for insertion of the guide tube 4. This may not be necessary if a rigid guide tube 4 is used, but it may be preferable to form a pathway in a controlled and minimally traumatic manner.

[0180] The probe 60 is equipped with a rod 62 at its distal end, and the rod 62 has a round or conical distal end 64. The rod 62 is further provided with a spike 66 extending axially from its distal end. The spike 66 has a smaller diameter than the rod 62, and its most distal end is configured to cut brain tissue. The spike 66 may have a rounded most distal end. The spike 66 may taper from the point where it connects to the rod 62 at the rounded distal end of the rod to its most distal end. The maximum diameter of the spike 66 may be less than or equal to the diameter of the fluid transfer tube 6, preferably less than its diameter.

[0181] The outer diameter of the probe 60 must be at most the same as the outer diameter of the guide tube 4. The section 62 of the probe 60 that forms the section of the path where the seal area 70 exists during use must be less than or equal to the diameter of the guide tube 4 within the reduced pressure area 72. For example, to achieve this, the probe 60 can be configured such that the diameter of its distal end is smaller than the diameter of its proximal end, as shown in Figure 22. The outer diameter of the probe 60 can be the same as or less than the outer diameter of the guide tube 4, except for its smaller-diameter distal end 64 and spike 66.

[0182] When in use, inserting the spike 66 at the distal end of the probe 60 allows for tissue incision while minimizing trauma. This reduces the resistance path of the round or conical distal end 64, expanding the tissue to the larger diameter of the rod 62 and creating a path with minimal tissue trauma.

[0183] To create a path for use in the guide tube described above, the diameter of the probe 60 may be 1.2 mm or less. The diameter of the rod 62 may be smaller than the diameter of the probe 60 proximal to the rod 62. The diameter of the rod 62 is at least 0.1 mm smaller than the diameter of the probe 60 proximal to the rod 62, for example, the diameter of the rod 62 is 1.1 mm or less. The length of the rod 62 may be less than or equal to the length of the seal area 70. The length of the rod 62 may be approximately equal to the length of the seal area 72. The length of the spike 66 is 4 mm to 5 mm, and it may taper from 0.6 mm or 0.5 mm where it connects to the rod 62 to 0.3 mm or 0.2 mm at the distal end. For example, the spike 66 may taper from 0.5 mm where it connects to the rod 62 to 0.3 mm at the distal end. If the probe 60 has an outer diameter of 1.2 mm, the diameter of the pathway generated in the brain tissue tends to be slightly smaller (e.g., 1.1 mm) after the probe is removed.

[0184] The probe 60 can be made from a rigid material such as hardened stainless steel or tungsten carbide. The probe 60 may be coated to enhance lubricity, such as PTFE or parylene. The shape of the probe 60 is designed to pass through brain tissue accurately and with minimal trauma to reach the target, thereby making the subsequent insertion of the guide tube 4 relatively trauma-free. The shape of the probe 60 is also designed to gently expand the tissue to form a pathway and enable tissue sealing, rather than crushing the tissue. In addition to providing a means of creating a pathway for the guide tube 4, the spike 66 of the probe can also be used to form a pathway for the fluid transfer tube 6 beyond the end of the guide tube 4.

[0185] The probe 60 may be provided as part of a kit for convection-enhanced delivery of an injectable fluid into the brain parenchyma. The kit may include the probe 60 for insertion into brain tissue and a guide tube 4. The kit may also include a guide hub 50 and / or a fluid transfer tube 6 for attachment into the brain via the guide tube. The kit may further include the delivery probes described below.

[0186] In particular, if the guide tube 4 is flexible, the guide tube 4 can be inserted into the brain via a delivery probe using stereotactic guidance before the proximal end 28 of the guide tube 4 is fixed in or near the skull, preferably within the guide hub 50.

[0187] The delivery probe is configured to be inserted into a through-hole 30 of the guide tube 4. The guide tube 4 is inserted into the brain with the delivery probe attached. To deliver the guide tube 4 to a predetermined position, the delivery probe can be shaped to engage with the proximal end 28 of the guide tube 4. For example, the delivery probe may have a larger diameter at the proximal end, forming a "step" on the outer surface of the delivery probe that engages with the nearest end of the guide tube 4. If the guide tube 4 has a laminated structure and there is no inner layer 26 in the proximal portion 38, the delivery probe may have two steps, as described above. The distal step engages with the upper part of the inner layer 26 and provides insertion force. The other step (the proximal step) may engage with the outermost end of the proximal portion 38 and be positioned to compress the proximal portion. Typically, this compression is small, for example, 1-3 mm, when the length of the proximal portion 38 is about 1-1.5 cm. This compression during insertion applies a slight preload to the proximal portion 38, making it easier to lengthen the proximal portion 38 when the distance from the skull to the brain increases.

[0188] When the delivery probe delivers the guide tube 4 into the brain, the distal end 18 of the guide tube 4 is positioned at a predetermined target location within the brain. The distal end of the delivery probe may be configured to cut brain tissue. In this case, the delivery probe can advance further along the same trajectory as the guide tube 4, and its distal end can reach the intended location of the fluid transfer tube 6, forming a pathway for the fluid transfer tube 6. The delivery probe is then withdrawn, leaving the guide tube 4 in its original position and a distal pathway for accommodating the fluid transfer tube.

[0189] A surgical method using the apparatus described herein is described below. The method for implanting a guide tube for convection-enhancing delivery of an injectable fluid into the brain parenchyma includes inserting the guide tube 4 into the brain until its distal end reaches a planned location in the brain. The guide tube 4 comprises a through-hole 30 for passing the fluid transport tube 6 through, and a distal end 18 with a sealing region 70. The guide tube 4 may be the guide tube 4 described above. As the guide tube 4 is inserted into the brain with the help of a delivery probe passing through the through-hole 30 of the guide tube 4 as described above, the distal end of the delivery probe will be located at or slightly beyond the distal end 18 of the guide tube 4. Insertion of the guide tube 4 can be performed with the delivery probe positioned in the through-hole 30 such that the distal end 18 of the delivery probe extends to or slightly beyond the distal end 18 of the guide tube 4. This method may further include cutting the guide tube 4 to a desired insertion length relative to the fixation point of the skull before inserting the guide tube 4 into the guide tube path.

[0190] The method further includes the steps of compressing brain tissue adjacent to the seal region 70 to form an anti-reflux seal around the distal end 18 of the guide tube 4, and forming a decompression region 72 in which the compression of brain tissue is lower than the compression of brain tissue in both the proximal and distal adjacent regions of the decompression region.

[0191] When brain tissue adjacent to the sealing region 70 is compressed to form a backflow prevention seal, a decompression region 72 is also formed, i.e., the backflow prevention seal is at least partially formed by the decompression region 72. Compression of brain tissue and formation of the decompression region 72 can be achieved using one or more features on the outer diameter of the guide tube 4. These features include a change in the outer diameter of the guide tube 4 in the sealing region 70, thereby changing the outer diameter of the guide tube 4 in the sealing region 70. For example, the decompression region 72 may be provided by one or more grooves on the outer surface of the guide tube 4, one or more projections 94 from the outer surface of the guide tube 4, or a combination of one or more projections and one or more grooves.

[0192] This method may include inserting a probe 60 into the brain parenchyma to form a guide tube pathway before inserting the guide tube into the brain. The guide tube pathway extends to a planned location in the brain where the distal end of the guide tube 4 is to be positioned. The diameter of the guide tube 4 may be at least the same as the diameter of the probe 60. The probe 60 may comprise a rod 62 having a round or conical distal end 64 as described above, and a spike 66 extending axially from the distal end 64 of the rod 62. The spike 66 may have a smaller diameter than the rod 62 and have a distal end configured to incise brain tissue.

[0193] Once the guide tube 4 is implanted, it can be used to deliver the injectable fluid to the brain. The convection-enhanced delivery method of the injectable fluid to the brain parenchyma may include implanting the guide tube 4 in the brain, as described above.

[0194] This method may further include advancing the delivery probe through a through-hole 30 along the axis of the guide tube 4 to form a fluid transport tube pathway within the brain tissue located at the distal end 18 of the guide tube 4. A fluid transport tube 6 is housed in this fluid transport tube pathway extending through the brain tissue distal to the guide tube 4. The diameter of the fluid transport tube pathway may be narrower than the diameter of the guide tube pathway. Once the distal end of the guide tube 4 reaches the planned position and the fluid transport tube pathway is formed, the delivery probe can be removed while the guide tube 4 remains in the brain.

[0195] Instead of passing the delivery probe through the through-hole 30, the fluid transfer tube route may be created by the following steps: i) removing the delivery probe when the distal end 18 of the guide tube 4 is in the planned position; ii) inserting the routing probe along the trajectory of the guide tube 4, beyond the distal end 18 of the guide tube 4, to create a fluid transfer tube route through the brain tissue; and iii) removing the routing probe.

[0196] This method may further include passing the fluid transfer tube 6 through the through-hole 30 of the guide tube 4 and guiding it along the fluid transfer tube path into the brain, and delivering the injectable fluid into the brain via the fluid transfer tube. The injectable fluid can carry any suitable therapeutic agent, inert fluid, contrast agent, or diagnostic agent that can be delivered to brain tissue via a suitable biologically inert fluid. In this case, the guide tube 4 is preferably configured to vent gas from the through-hole 30 through a porous layer, for example, as described above.

[0197] Alternatively, a convection-enhanced delivery method for an injectable fluid into the brain parenchyma may include implanting a guide tube 4 into the brain, and inserting the guide tube 4 into the brain includes inserting the guide tube 4 together with a fluid transfer tube 6 in a through-hole 30 and delivering the injectable fluid to the brain via the fluid transfer tube. This is particularly suitable for a guide tube 4 that is rigid and does not require a pre-formed guide tube path before insertion, as shown in Figure 5. Preferably, a positive pressure of the injectable fluid is provided in the fluid transfer tube 6 while the guide tube 4 is being inserted. This prevents perforation of brain tissue by the fluid transfer tube 6 and also prevents the introduction of air that may occur if the fluid transfer tube 6 is inserted while filled with gas.

[0198] Each of the guide tube 4, delivery probe, routing probe, and fluid transfer tube may include any of the features described herein in relation to other aspects.

[0199] Further details of the method are provided in the following numbered sections.

[0200] M1. A method is provided for implanting a guide tube for convective-enhanced delivery of an injectable fluid into the brain parenchyma. The method comprises inserting the guide tube into the brain until the distal end of the guide tube reaches a planned location in the brain, the guide tube comprising a through-hole for passing a fluid transport tube and a distal end including a sealing region, the method further comprises compressing brain tissue adjacent to the sealing region to form a backflow-inhibiting seal around the distal end of the guide tube, and the compression of the brain tissue forming a decompression region where the compression of the brain tissue is lower than the compression of the brain tissue in both the proximal and distal adjacent regions of the decompression region.

[0201] M2. The method of item M1, further comprising inserting a probe into the brain parenchyma to form a guide tube pathway extending to a planned location before inserting the guide tube into the brain, wherein the guide tube has at least the diameter of the probe, and inserting the guide tube into the brain comprises inserting the guide tube into the guide tube pathway.

[0202] M3. A convection-enhanced delivery method for an injectable fluid into the brain parenchyma, comprising: implanting a guide tube in the brain using the method of item M1 or M2; advancing a delivery probe through a through-hole along the axis of the guide tube to form a fluid transport tube pathway extending from the distal end of the guide tube; passing the fluid transport tube through the through-hole of the guide tube and through the fluid transport tube pathway into the brain; and delivering the injectable fluid to the brain via the fluid transport tube.

[0203] M4. A convection-enhanced delivery method of an injectable fluid into the brain parenchyma, comprising implanting a guide tube in the brain using the method of item M1 or M2, wherein the insertion of the guide tube into the brain comprises inserting the guide tube together with a fluid transfer tube in a through-hole, preferably providing positive pressure of the injectable fluid in the fluid transfer tube during the insertion of the guide tube, and the method further comprises delivering the injectable fluid into the brain via the fluid transfer tube.

[0204] M5. A method according to item M2 or any of the preceding items relating thereto, wherein the probe comprises a rod having a round or conical distal end, and a spike extending axially from the distal end of the rod, the diameter of the spike being narrower than that of the rod, and the most distal end of the spike being configured to cut brain tissue.

[0205] M6. The method of item M3, wherein the guide tube is inserted with the delivery probe in the through-hole, and the distal end of the delivery probe extends to or slightly beyond the distal end of the guide tube.

[0206] M7. A method according to item M3 or any of the preceding items relating thereto, wherein the diameter of the fluid transfer tube path is narrower than the diameter of the guide tube path.

[0207] M8. Any method described in sections M1 to M7, further comprising cutting the guide tube to a desired insertion length relative to a fixation point within the skull before inserting the guide tube into the brain.

Claims

1. A guide tube used in conjunction with a fluid transfer tube to provide fluid access to the brain of a mammal, wherein the guide tube is configured to be inserted into the brain. A through-hole for the fluid transfer tube to pass through, The distal end and Equipped with, The distal end of the guide tube includes a sealing region configured to compress the surrounding brain tissue and form a backflow prevention seal around the distal end of the guide tube. The sealing region comprises a decompression region in which the compression of brain tissue is lower than the compression of brain tissue in both the proximal and distal adjacent regions. Guide tube.

2. The guide tube according to claim 1, wherein the sealing region comprises a plurality of pressure reduction regions.

3. The guide tube according to claim 2, wherein the plurality of depressurization regions are arranged at equal intervals along the length of the guide tube.

4. The guide tube according to claim 2 or 3, wherein the spacing between the reduced pressure regions is a maximum of 2 mm, preferably a maximum of 1.5 mm, and more preferably a maximum of 1 mm.

5. The guide tube according to any one of claims 2 to 4, wherein the reduced pressure region is provided over at least 5% of the length of the guide tube.

6. The guide tube according to any one of claims 2 to 5, wherein the reduced pressure region is provided over a length of at least 2 mm of the guide tube.

7. The guide tube according to any one of claims 1 to 6, wherein at least one of the depressurization regions is located up to 20 mm away from the most distal end of the guide tube.

8. The guide tube according to any one of claims 1 to 7, wherein at least one of the depressurization regions is located up to 25% of the length of the guide tube from the most distal end of the guide tube.

9. The guide tube according to any one of claims 1 to 8, wherein the reduced pressure region is provided by grooves on the outer surface of the guide tube or between projections from the outer surface of the guide tube.

10. The guide tube according to claim 9, wherein the depth of the groove is a maximum of 0.5 mm, or the height of the projection is a maximum of 0.5 mm, and / or the depth of the groove is at least 0.1 mm, or the height of the projection is at least 0.1 mm.

11. The guide tube according to claim 9 or 10, wherein the groove or projection extends over the entire circumference of the guide tube.

12. The guide tube according to any one of claims 1 to 11, wherein the outer surface of the guide tube is configured to come into contact with brain tissue after the guide tube is inserted into the brain.

13. The guide tube according to any one of claims 1 to 12, wherein the outer surface of the guide tube is provided with a lubricating coating such as parylene or PTFE.

14. The guide tube according to any one of claims 1 to 13, wherein the distal end of the guide tube is round, bullet-shaped, or conical.

15. The guide tube according to any one of claims 1 to 14, wherein the diameter of the distal end of the guide tube is a maximum of 2.5 mm, preferably 1.8 mm, more preferably a maximum of 1.6 mm, and most preferably a maximum of 1.3 mm.

16. The guide tube according to any one of claims 1 to 15, wherein the diameter of the through hole of the guide tube is 0.2 mm to 1 mm, preferably 0.4 mm to 0.7 mm, and more preferably 0.5 mm to 0.6 mm.

17. The guide tube according to any one of claims 1 to 16, wherein the guide tube comprises a hard material such as ceramic, metal, or hard plastic.

18. The guide tube according to claim 17, wherein the length of the guide tube is 50 mm to 300 mm, preferably 100 mm to 250 mm.

19. The guide tube according to claim 17 or 18, wherein the guide tube has a proximal end configured to be guided and / or held by a stereoguide or robotic guide while the guide tube is inserted into the brain and / or while the guide tube is used to deliver an injectable fluid to the brain.

20. The guide tube according to claim 19, wherein the proximal end of the guide tube has a larger diameter than the distal end of the guide tube, and optionally the diameter of the proximal end of the guide tube is up to 7 mm, preferably up to 6 mm, and more preferably up to 5 mm.

21. The guide tube according to any one of claims 1 to 20, wherein the material and / or thickness of the guide tube is such that it can be cut by hand using a knife.

22. The guide tube according to any one of claims 1 to 21, wherein the guide tube comprises a porous layer that allows air to pass through, and the porous layer comprises a hydrophobic material, optionally a superhydrophobic material.

23. The guide tube according to claim 22, wherein the porous layer comprises at least one of sintered polytetrafluoroethylene, sintered polyurethane, stretched polytetrafluoroethylene, silicone foam, polyurethane foam, shape memory polymer, microporous hollow extruded polymer fiber, or electrospun polymer.

24. The guide tube according to claim 23, wherein the microporous hollow extruded polymer fiber and / or the electrospun polymer comprises at least one of polytetrafluoroethylene, polyvinylidene fluoride, polyurethane, polypropylene, and copolymers thereof.

25. The guide tube according to any one of claims 22 to 24, wherein the porous layer comprises heterogeneous materials having different rigidities and / or a plurality of materials having different rigidities, and optionally the rigidity of the porous layer is greater near or to the through-hole.

26. The guide tube according to claim 25, wherein the porous layer includes at least an inner layer and an outer layer, the inner layer is more rigid than the outer layer, and the inner layer is configured to allow air to pass through it.

27. The guide tube according to claim 26, wherein the inner layer comprises a plurality of holes penetrating the inner layer and / or is made of a material porous to air.

28. The guide tube according to claim 26 or 27, wherein the inner layer is the innermost layer of the guide tube and provides the surface of the through hole.

29. The guide tube according to any one of claims 26 to 28, wherein the inner layer comprises at least one of polyether ether ketone; nylon; polyurethane; polyester; fluoropolymers such as polytetrafluoroethylene; polymer perfluoroethers such as perfluoroalkoxyalkanes, polyvinylidene difluoride, and fluorinated ethylene propylene; liquid crystal polymers; and mixtures or copolymers thereof.

30. The guide tube according to any one of claims 26 to 29, wherein the inner layer is manufactured by a process comprising at least one of sintering, extrusion with microparticle leaching, micro-perforation of the tube by drilling or laser; weaving, knitting or electrospinning polymer fibers around a cylindrical mold to form a tube of porous polymer material; and 3D printing of the polymer in a porous form.

31. The guide tube according to any one of claims 22 to 30, wherein the porous layer is the outermost layer of the guide tube.

32. The guide tube according to any one of claims 22 to 30, further comprising a fluid-impermeable coating layer provided on the porous layer, optionally the coating layer being lubricating, and further optionally the coating layer including a heat-shrinkable tube.

33. The guide tube according to claim 32, wherein the reduced pressure region is provided by the coating layer, and optionally the coating layer includes a heat-shrinkable tube having a series of axial, optionally annular, thickened or grooved portions applied on the porous layer.

34. The guide tube according to any one of claims 1 to 16, 21 to 33, wherein the guide tube is flexible.

35. The guide tube according to claim 34, wherein at least the proximal portion of the guide tube is elastically deformable along the axial direction.

36. The guide tube comprises at least an inner layer and an outer layer, wherein the inner layer is more rigid than the outer layer, and the outer layer is elastically deformable. The guide tube according to claim 35, wherein the inner layer does not extend to the proximal portion of the guide tube.

37. The guide tube comprises at least an inner layer and an outer layer, wherein the inner layer is more rigid than the outer layer, and the outer layer is elastically deformable. The guide tube according to claim 35, wherein the inner layer is configured to provide a spring in the proximal portion of the guide tube.

38. The guide tube according to any one of claims 1 to 37, wherein the proximal end of the guide tube includes an enlarged portion configured to be fixed into a trepanation hole in the skull.

39. The guide tube according to claim 38, wherein the enlarged portion comprises a large-diameter portion configured to engage with a guide hub for fixing to the skull.

40. The guide tube according to claim 39, wherein a fluid seal is formed between the guide tube and the guide hub by engaging the large-diameter portion of the guide tube with the guide hub.

41. The guide tube according to claim 39 or 40, wherein the guide tube comprises an elastically deformable outer layer, and the engagement of the large-diameter portion of the guide tube with the guide hub includes compression of the outer layer.

42. The guide tube according to any one of claims 39 to 41, wherein the diameter of the through hole of the guide tube in the large-diameter portion increases toward the proximal end of the large-diameter portion.

43. The guide tube according to any one of claims 39 to 42, wherein the large-diameter portion comprises a non-compliant core located inside the outer layer, and optionally the large-diameter portion is overmolded on the rigid inner layer.

44. The guide tube according to any one of claims 39 to 43, wherein the non-compliant core is configured to ensure a gas path through the non-compliant core, and optionally the non-compliant core comprises a porous material such as sintered polyurethane or PEEK, and / or an air vent channel.

45. The guide tube according to claim 43 or 44, wherein the non-compliant core is disposed inside the outer layer.

46. The non-compliant core is located outside the inner layer or is formed integrally with the inner layer. As an option, the inner layer does not extend to the nearest end of the large diameter portion. Furthermore, as an option, the inner layer extends up to 80% of the large diameter portion, and optionally up to 60%. A guide tube according to any one of claims 43 to 45 that is dependent on claim 26.

47. A neurosurgical device, The guide tube according to claim 39 or any one of the previously stated claims relating thereto, A guide hub for fixing the guide tube to the patient's skull before insertion into the brain, Equipped with, The guide hub is provided with a passage through which the guide tube passes. Neurosurgical equipment.

48. A neurosurgical device, The guide tube according to any one of claims 1 to 46, A fluid transfer tube, preferably a cannula, is configured to be inserted into the through-hole of the guide tube, A neurosurgical device equipped with [a specific feature].

49. A neurosurgical device, The guide tube according to any one of claims 1 to 46, A probe configured to be inserted into brain tissue, Equipped with, The aforementioned probe A rod having a round or conical distal end, A spike extending axially from the distal end of the rod, Equipped with, The diameter of the spike is narrower than that of the rod, and the distal end of the spike is configured to cut brain tissue. Neurosurgical equipment.

50. A neurosurgical device, The guide tube according to any one of claims 1 to 46, A delivery probe configured to be inserted into the through-hole of the guide tube, Equipped with, The distal end of the delivery probe is configured to cut brain tissue. Neurosurgical equipment.

51. A method for implanting a guide tube for convection-enhanced delivery of an injection fluid into the brain parenchyma, This includes inserting the guide tube into the brain until its distal end reaches a planned location within the brain. The guide tube comprises a through hole for passing the fluid transfer tube, and a distal end including a sealing region. The above method further, Compress the brain tissue adjacent to the seal region to form a backflow-inhibiting seal around the distal end of the guide tube, To form a reduced pressure region, Includes, The compression of brain tissue in the decompression region is lower than the compression of brain tissue in both the proximal and distal adjacent regions of the decompression region. method.

52. The method according to claim 51, The method further includes inserting a probe into the brain parenchyma to form a guide tube pathway extending to the planned location before inserting the guide tube into the brain, The guide tube has at least the diameter of the probe, and inserting the guide tube into the brain includes inserting the guide tube into the guide tube pathway. method.

53. A method for delivering an injected fluid to the brain parenchyma with enhanced convection, Implanting a guide tube in the brain using the method of claim 51 or 52, The delivery probe is advanced along the axis of the guide tube through the through hole to form a fluid transfer tube path extending from the distal end of the guide tube, The fluid transfer tube is passed through the through-hole of the guide tube and routed through the fluid transfer tube path into the brain. The injection fluid is delivered to the brain via the fluid transfer tube, including, method.

54. A method for delivering an injected fluid to the brain parenchyma with enhanced convection, The method includes implanting a guide tube in the brain using the method described in claim 51 or 52, Inserting the guide tube into the brain includes inserting the guide tube together with the fluid transfer tube in the through-hole, preferably, providing positive pressure of the injection fluid into the fluid transfer tube during insertion of the guide tube. The above method further, This includes delivering the injected fluid into the brain via the fluid transfer tube. method.

55. A method according to claim 52 or any one of the previously stated claims relating thereto, The aforementioned probe A rod having a round or conical distal end, A spike extending axially from the distal end of the rod, Equipped with, The diameter of the spike is narrower than that of the rod, and the distal end of the spike is configured to cut brain tissue. method.

56. The method according to claim 53, The insertion of the guide tube is performed with the delivery probe placed inside the through-hole, and the distal end of the delivery probe extends to the distal end of the guide tube, or slightly beyond the distal end of the guide tube. method.

57. A method according to claim 53 or any one of the previously stated claims relating thereto, The diameter of the fluid transfer tube path is narrower than the diameter of the guide tube path. method.

58. A method according to any one of claims 51 to 57, The process further includes cutting the guide tube to a desired insertion length relative to a fixation point within the skull before inserting the guide tube into the brain. method.

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