Micro-molding device and system for making a catheter for reducing or preventing backflow in a delivery system

Contents of disclosure

0001[Cross-reference of related applications] This application claims priority to US Provisional Patent Application No. 61 / 738,850 filed December 18, 2012, and US Provisional Patent Application No. 61 / 835,912 filed June 17, 2013. , Each of which is incorporated herein by reference in its entirety.

0002[Field] The present invention relates to systems and methods for reducing or preventing backflow in delivery systems such as convection-enhanced delivery systems that deliver therapeutic agents to patients.

0003[background] In convection enhanced delivery (CED), the drug is injected locally into the tissue through a needle, cannula, or microcatheter inserted into the tissue. The transport of the infused material is governed by convection, which enhances the penetration of the drug into the target tissue compared to delivery via application or systemic delivery.

0004CED has emerged as a leading investigational delivery technique for the treatment of several diseases. Clinical trials using existing equipment have shown varying results, with treatment outcomes within the target tissue determined by the rate of injection, the relative ratio of convection to release during CED, and the various properties of the target tissue. It has been suggested that it is strongly dependent on the degree of penetration and distribution of the drug into.

0005As the infusion rate increases, there may be a tendency for the infused fluid to flow back along the insertion path between the outside of the microcatheter and the surrounding tissue. Flexible microcatheter designs have been constructed to reduce the regurgitation of this drug-containing fluid. However, fluid regurgitation during CED treatment remains a significant problem in clinical practice. This is especially true for CED in the brain, as the poroelastic nature of brain tissue contributes to regurgitation or reflux. Therefore, there is a need for improved CED devices, such as CED devices that reduce or eliminate the backflow of injected fluid between the outside of the device and the surrounding tissue.

0006[Overview] Systems and methods generally associated with CED devices with various features to reduce or prevent regurgitation are disclosed herein. In some embodiments, the CED device comprises a tissue receiving space located proximal to the distal fluid outlet. When the device is inserted into the patient's target area, the tissue can be compressed into the tissue receptive space or tightened / pinned by the tissue receptive space, thereby draining from the outlet. A seal is formed that reduces or prevents the fluid from flowing back proximally across the tissue receiving space. In some embodiments, the CED device comprises a bullet-shaped nose, proximal to the distal fluid outlet. This bullet-shaped nose forms a good seal with the surrounding tissue and helps reduce or prevent regurgitation of the injected fluid.

0007In some embodiments, a convection enhanced delivery (CED) device is provided, which extends along the proximal, central, distal, proximal, central, and distal portions. It comprises a microtip with at least one fluid channel, the at least one fluid channel having an outlet port at its distal end and an inlet port at its proximal end. The device is also a first outer sheath coaxially disposed over the distal portion of the microtip, the distal portion of the microtip protruding from the distal end of the first outer sheath. , A first tissue receiving space defined between the outer sheath of the first outer sheath and the outer surface of the microtip and the inner surface of the distal end of the first outer sheath, and proximal to the microtip. At least one fluid channel at the microtip, including an extending catheter body, communicates fluidly with the respective medial lumen of the catheter body. The device also includes a nose portion that is located at least on the central portion of the microtip and extends between the first outer sheath and the catheter body, the nose portion corresponding to the outer diameter of the first outer sheath. Reduced distal It defines an outer surface that tapers from diameter) to an enlarged proximal diameter that corresponds to the outer diameter of the catheter body.

0008The tissue receptive space can be configured to compress the tissue received within the tissue receptive space as the device advances through the tissue. Tissue compressed by the tissue receptive space can form a seal that reduces the flow of fluid drained from the outlet port of at least one fluid channel proximally across the tissue receptive space. The device may include a second outer sheath placed on top of the first outer sheath, with a second tissue receiving space on the outer surface of the first outer sheath and the distal end of the second outer sheath. It is defined between the inner surface of the part. The inner surface of the distal end of the first outer sheath can be shaped to compress the tissue received within the inner surface as the device advances through the tissue. The inner surface of the distal end of the first outer sheath may be conical, convex, and / or concave.

0009The inner diameter of the distal end of the first outer sheath may be about 1 μm to about 200 μm larger than the outer diameter of the distal portion of the microtip. The inner diameter of the distal end of the first outer sheath may be about 10% to about 100% larger than the outer diameter of the distal portion of the microtip. The first outer sheath may have a circular outer cross section. At least one fluid channel can be formed from at least one of a parylene composition, a silastic composition, a polyurethane composition, and a PTFE composition. The device may include a fluid reservoir that is in fluid communication with the inner lumen of the catheter body and is configured to supply fluid to the inner lumen under positive pressure. The microtip may be flexible. The microtip may include an embedded microsensor.

0010Embedded microsensors are interrogatable sensors, pressure sensors, glutamate sensors, pH sensors, temperature sensors, ion concentration sensors, carbon dioxide sensors, oxygen sensors, and lactate sensors. Can include at least one of sensors). The distal end of the microtip can have a non-traumatic shape configured to penetrate the tissue without causing trauma. The microtips can contain a certain amount of drug, can be coated with the drug, and / or can be impregnated with the drug. The agent may include at least one of an antibacterial agent, an anti-inflammatory agent, a corticosteroid, and a dexamethasone. The microtip may include a substrate, on which at least one fluid channel is formed. The substrate may have a rectangular cross section. The catheter body may be made of a rigid material. Each medial lumen of the catheter body can be defined by a sleeve made of flexible material. The catheter body can be formed from at least one of ceramic, PEEK, and polyurethane. Each sleeve can be formed from at least one of polyimide, pevacs, PEEK, polyurethane, silicone, and fused silica. The catheter body can be formed from a flexible material. A nose portion is formed on the first outer sheath to form a nose portion, a microtip portion is inserted into the proximal end portion of the nose portion, the proximal portion of the microtip portion is connected to the catheter body, and the nose is formed. The device can be assembled by injecting a fluid material through an inlet port formed in the portion to fill the inside of the nose portion and fixing the microtip and catheter body to the nose portion.

0011In some embodiments, a convection enhanced delivery (CED) device is provided, which is a fluid conduit having proximal and distal ends and a first outer sheath coaxially located on the fluid conduit. A first outer sheath in which the fluid conduit extends from the distal end of the first outer sheath, and an outer surface of the fluid conduit and an inner surface of the distal end of the first outer sheath. Includes a first tissue receiving space defined between them.

0012In some embodiments, a micro-molding device is provided that includes a catheter body and a molding cavity sized and configured to receive the catheter microtip into the microtip. At least one fluid channel of the portion is at least partially located within the corresponding fluid line of the catheter body. The device also includes one or more molding channels through which the molding fluid can be injected to fill the molding cavity and secure the microtip to the catheter body, at least one of the microtips. One fluid channel communicates with at least one fluid line in the catheter body. The device may be transparent to allow UV light to cure in order to cure the molding fluid placed inside the molding cavity. The molding cavity can be sized and configured to form a bullet-shaped nose portion above the microtip and at least a portion of the outer sheath received within the molding cavity.

0013In some embodiments, a method of delivering a therapeutic agent to a patient is provided. In this method, a fluid conduit surrounded by a first outer sheath is advanced into the tissue and defined between the outer surface of the fluid conduit and the inner surface of the distal end of the first outer sheath. It involves compressing the tissue into the first tissue receiving space. The method also includes delivering the fluid containing the therapeutic agent under positive pressure through the fluid conduit into a portion of tissue adjacent to the distal end of the fluid conduit.

0014This method seals through a fluid conduit before delivering the fluid containing the therapeutic agent. The gel) may be delivered to fill one or more gaps between the fluid conduit and the tissue. The tissue compressed into the first tissue receptive space can form a seal that reduces the fluid drained from the distal end of the fluid conduit from regurgitating proximally across the tissue receptive space. .. The method may include advancing the second outer sheath, which is placed on the first outer sheath, into the tissue, where the tissue is of the outer surface of the first outer sheath and of the second outer sheath. It is compressed into a second tissue-receptive space defined between the inner surface of the distal end. The inner surface of the distal end of the first outer sheath may be at least one of cylindrical, conical, convex, and concave. This method may include controlling the delivery of fluid through the fluid conduit based on the output of a microsensor embedded in the fluid conduit. This method involves central nervous system (CNS) tumors, intractable epilepsy, Parkinson's disease, Huntington's disease, stroke, lithosome accumulation, chronic brain damage, Alzheimer's disease, muscular atrophic sclerosis, balance disorder, hearing loss. , And can be used to treat at least one disease selected from spongy malformations. Advancement of the fluid conduit may include bringing the nose portion into contact with the tissue, the nose portion extending between the first lateral sheath and the proximal catheter body, and the nose portion being the first. It tapers from a small distal diameter corresponding to the outer diameter of the outer sheath to a proximal enlargement corresponding to the outer diameter of the catheter body. The fluid conduit may be connected to the distal end of the flexible catheter, the method of inserting the catheter through an incision and using stereotactic targeting to bring the fluid conduit closer to a portion of the tissue. Positioning, removing the stylet inserted through the catheter, squeezing the proximal end of the catheter under the patient's scalp, and fluidizing one or more proximal fluid connectors of the catheter. It may include connecting to a delivery system.

0015The present invention further provides devices, systems, and methods as described in the claims.

0016The present invention will be further fully understood from the following detailed description, which will be construed in conjunction with the accompanying drawings.

0017[Detailed explanation] An exemplary embodiment is described to provide an overall understanding of the principles of structure, function, manufacture, and use of the methods, systems, and devices disclosed herein. One or more embodiments of these embodiments are shown in the accompanying drawings. The methods, systems, and devices specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments, and the scope of the invention is defined only by the claims. Will be understood by those skilled in the art. Features exemplified or described in connection with one exemplary embodiment may be combined with features of another embodiment. Such modifications and modifications are intended to be within the scope of the present invention.

0018Systems and methods generally associated with CED devices with various features for reducing or preventing regurgitation are disclosed herein. In some embodiments, the CED device comprises a tissue receiving space located proximal to the distal fluid outlet. Tissue can be compressed into the tissue receptive space or tightened / pinned by the tissue receptive space when the device is inserted into the patient's target area, thereby draining from the outlet. It forms a seal that reduces or prevents fluid from flowing back proximally across the tissue receptive space. In some embodiments, the CED device comprises a bullet-shaped nose proximal to the distal fluid outlet. The bullet-shaped nose forms a good seal with the surrounding tissue and helps reduce or prevent regurgitation of the injected fluid.

0019FIG. 1 shows one exemplary embodiment of the CED apparatus 10. The device 10 generally includes a fluid conduit 12 and an outer sheath 14. The outer sheath 14 may be coaxially disposed over the fluid conduit 12, which extends from the distal end 16 of the outer sheath 14. The fluid conduit 12 and the outer sheath 14 are sized and sized so that the tissue receiving space 18 is formed between the outer surface of the fluid conduit 12 and the inner surface of the distal end 16 of the outer sheath 14. ..

0020The fluid conduit 12 can define one or more fluid lumens extending approximately parallel to the central length direction axis of the device 10. The fluid conduit 12 may include a fluid inlet port (not shown in FIG. 1) and a fluid outlet port 20. Although a single fluid outlet port 20 is shown in the illustrated embodiment, the device provides multiple fluid outlet ports, as well as multiple fluid inlet ports, and between the fluid outlet port and the fluid inlet port. It will be appreciated that it may include multiple fluid lumens that extend. The fluid inlet port may be located at the proximal end of device 10, for example, fluid storage of fluid conduit 12 via one or more catheters, pumps, instruments, valves, or other suitable controls. It can communicate with the vessel. Such a control device can be used to regulate the pressure at which the fluid is supplied to the device 10 or the velocity or volume of the fluid supplied to the device 10.

0021The fluid supplied to the conduit 12 through the fluid inlet port can be directed through one or more inner lumens of the conduit 12 and can also be discharged through one or more fluid outlet ports 20. The fluid outlet port 20 can be sized, shaped and / or positioned to control various discharge parameters of the fluid. For example, the fluid outlet port 20 may be configured to control the direction in which the fluid is discharged from the device 10, the distribution of the fluid within the target tissue, and the rate or pressure at which the fluid is discharged. In an exemplary embodiment, the size of the fluid outlet port may gradually increase towards the distal end of device 10, which can advantageously offset the pressure loss that occurs along the length of the device. The fluid can be discharged from each of the multiple fluid outlet ports at substantially the same pressure. The fluid outlet port may also be located at various points around the perimeter of the fluid conduit 12 or may be shaped to control the direction of fluid discharge.

0022The fluid conduit 12 and / or the outer sheath 14 may have a circular outer cross section, which advantageously allows the device 10 to create a large gap with the outside of the device that can cause trauma and increase regurgitation. It can rotate inside the tissue without forming between it and the surrounding tissue. The fluid conduit 12 may be flexible so that it can move with the tissue into which the fluid conduit is inserted. Although a generally cylindrical fluid conduit 12 is shown, the fluid conduit 12 may have a non-cylindrical or polygonal cross section. For example, as described below with respect to FIG. 7, the fluid conduit 12 may be a micromachined tip, which has a square or rectangular cross section with one or more fluid channels arranged. Includes the substrate to have. The interior of the outer sheath 14 may be molded to substantially correspond to the cross section of the fluid conduit 12. Alternatively, the outer sheath 14 may have an inner cross-sectional shape that is different from the outer cross-sectional shape of the fluid conduit 12. For example, the outer sheath 14 may have a substantially cylindrical internal cross-sectional shape at its distal end, whereas the fluid conduit 12 may have a substantially square or rectangular outer cross-sectional shape. Thereby, a tissue receiving space 18 is defined between the outside of the fluid conduit 12 and the inside of the outer sheath 14.

0023As mentioned above, the outer sheath 14 may be coaxially arranged over the fluid conduit 12, which extends from the distal end 16 of the outer sheath 14. The clearance space between the outer surface of the fluid conduit 12 and the inner surface of the sheath 14 may define the tissue receiving space 18. For example, as shown in FIG. 2, the fluid conduit 12 may have an outer diameter D1 that is smaller than the inner diameter D2 of the outer sheath 14. To the extent that the diameter D2 exceeds the diameter D1, the amount of tissue that is compressed into the tissue receiving space 18 or tightened by the tissue receiving space 18 can be determined.

0024In some embodiments, an adhesive or other filler is placed between the fluid conduit 12 and the sheath 14 to hold the fluid conduit in a fixed longitudinal position with respect to the sheath and fluid. The conduit can be kept in the center of the sheath (eg, the tissue receiving space 18 has a uniform width around the periphery of the fluid conduit). For example, the tissue receiving space 18 may extend proximally by a first distance from the distal end 16 of the sheath 14, and behind that point the gap space between the fluid conduit 12 and the sheath 14 is filled. obtain. In some embodiments, the sheath 14 may have a stepped, tapered, or other similarly shaped interior so that a gap space is present along the distal portion of the sheath 14. There is no clearance along the proximal portion of the sheath 14.

0025In an exemplary embodiment, the inner diameter of the distal end 16 of the outer sheath 14 is about 1 μm to about 1000 μm, about 1 μm to about 500 μm, about 1 μm to about 200 μm, or about 1 μm from the outer diameter of the fluid conduit 12. It may be about 20 μm larger. In an exemplary embodiment, the inner diameter of the distal end 16 of the outer sheath 14 is about 5% to about 500%, about 5% to about 250%, about 10% to about 100 from the outer diameter of the fluid conduit 12. %, Or about 10% to about 20% larger. In an exemplary embodiment, the diameter D1 may be from about 50 μm to about 2000 μm, from about 50 μm to about 1000 μm, or from about 50 μm to about 200 μm. In an exemplary embodiment, the diameter D2 may be from about 51 μm to about 5000 μm, from about 55 μm to about 1000 μm, or from about 55 μm to about 200 μm. The tissue receiving space 18 is along the entire length of the outer sheath 14 or only a part of the outer sheath (for example, about 1 mm to about 100 mm, about 1 mm to about 50 mm, or about 1 mm to about 50 mm of the most distal part of the outer sheath. It may extend (along about 1 mm to about 10 mm).

0026The fluid conduit 12 and the outer sheath 14 can be formed from any of a variety of materials, including parylene compositions, silastic compositions, polyurethane compositions, PTFE compositions, silicone compositions and the like.

0027In some embodiments, the device 10 can be attached to a support scaffold (not shown) to provide structural rigidity to the device and facilitate insertion into target tissue. An exemplary support scaffold is "MULTI-DIRECTIONAL MICROFLUIDIC DRUG DELIVERY" Illustrated and illustrated in US Patent Application Publication No. 2013/0035560, filed August 1, 2012 under the name "DEVICE," the entire contents of which are incorporated herein by reference. To aid in tissue penetration and navigation, the distal end of the fluid conduit 12 and / or the distal end of the scaffold may be tapered, pointed, and / or sharpened. In some embodiments, the fluid conduit 12 and / or the scaffold is provided with a round non-traumatic tip to facilitate insertion through the tissue without causing trauma to the tissue. The supporting scaffold may be rigid or semi-rigid and may be formed from a degradable thermoplastic polymer, such as a degradable thermoplastic polyester or a degradable thermoplastic polycarbonate. In some embodiments, the supporting scaffold may be formed from poly (lactic acid-co-glycolic acid) (PLGA) and may be configured to biodegrade within the target tissue. This advantageously eliminates the possibility of interfering with the positioning of the fluid conduit 12 as the need to remove the supporting scaffold may be eliminated once the device 10 is positioned within the target tissue. Support scaffolds can also be formed using any of a variety of other materials, including silicon or various ceramics, metals, and plastics known in the art. The scaffold may have a width of about 100 μm to about 200 μm and may have a length that varies depending on the target tissue (eg, depending on the depth at which the target tissue is located). In one embodiment, the scaffold is 2 cm to 3 cm in length. Various techniques such as surface tension of water droplets, adhesive and / or biocompatible petrolatum can be used to connect the fluid conduit 12 and / or the outer sheath 14 to the supporting scaffold.

0028Either the fluid conduit 12, the outer sheath 14 and / or the supporting scaffold can contain or impregnate an amount of the drug. Alternatively, or in addition to this, the surface of these components may be coated with a chemical. Exemplary agents include anti-inflammatory ingredients, ingredients that increase the permeability of the agent, delayed release coatings and the like. In some embodiments, one or more components of device 10 can prevent swelling around the injection site and the disruption of fluid delivery patterns that can result from such swelling, corticosteroids such as dexamethasone. Can be coated with or impregnated with it.

0029The device 10 may include a fluid conduit 12, a sheath 14, or one or more sensors 22 mounted in or on a scaffold. Sensor 22 is a temperature sensor, pH sensor, pressure sensor, oxygen sensor, tension sensor, queryable sensor, glutamate sensor, ion concentration sensor, carbon dioxide sensor, lactate sensor, neurotransmitter sensor, or various other sensor types. Any of these may be included and feedback can be given to the control circuit, which regulates the delivery of fluid through device 10 based on the resulting sense of one or more parameters. can do. One or more electrodes 24 may be provided in or on the fluid conduit 12, sheath 14, or scaffold, which may stimulate the target tissue, eg, to deliver electrical energy to the target tissue. , Or it can be used to excise the target tissue. In one embodiment, electrical energy is delivered through the electrode 24 and the drug is simultaneously delivered through the fluid conduit 12.

0030FIG. 3 is a schematic view of the drug delivery system 26 including the device 10. The system 26 includes a reservoir 28 of drug-containing fluid, which is connected to the pump 30 via a control valve 32. When the control valve 32 is opened, the fluid in the reservoir 28 is supplied to the pressure regulator 34 under pressure by the pump 30, which can regulate the pressure at which the fluid is supplied to the device 10. A control valve 32, a pump 30, a regulator 34 may be operably coupled to a controller 36, which may include a microprocessor and memory, and a drug stored in a non-temporary computer-readable storage medium. It may be configured to run a delivery control program. The controller 36 opens and closes the valve 32, turns the pump 30 on and off, changes the output pressure of the pump 30, and / or adjusts the pressure setting point of the regulator 34. Can be configured. The controller 36 can also receive information indicating the sensed parameters via a feedback loop containing one or more sensors 22 mounted in or on the device 10. Thus, in response to feedback from one or more sensors 22 implanted with device 10, controller 36 initiates or stops the flow of fluid to device 10 to reduce the pressure at which the fluid is supplied to device 10. It can be increased or decreased, and so on. In one embodiment, device 10 includes a pressure sensor 22 that measures fluid pressure near device 10, and controller 36 brings the fluid supply pressure to a substantially constant level based on feedback from pressure sensor 22. Configured to keep.

0031Device 10 can be used for drug CED to treat diseases of the brain, spine, ears, nervous tissue, or other parts of the human or animal body. When used in the brain, device 10 can bypass the blood-brain barrier (BBB) by injecting the drug directly into the tissue under positive pressure. Device 10 can provide several advantages, including: 1) smaller cross-sectional area than conventional needles used in CED; 2) inserted into the brain compared to conventional needles. Less damage to tissue during; 3) Reduced or eliminated regurgitation or perfusion along the outside of the insertion site, which can increase the rate of drug delivery in device 10 compared to conventional needles. 4) Occlusion of the fluid delivery conduit 12 during insertion into the brain is minimal or does not occur; 5) Multiple lumens, each sending a separate fluid (drug), pass through the fluid conduit 12. 6) Equipment 10 can be provided as a drug delivery system and pressure, pH, ion-specific, allowing simultaneous, continuous, or programmed delivery of multiple substances. Concentration (ion-specific) Concentrations), location, and other parameters, but are not limited to these, may serve simultaneously as sensor-mounted probes for measuring local tissue features; 7) Device 10 directs drug release patterns. To enable.

0032During use, as described further below, device 10 can be functionally attached to the distal end of a long, thin insertion medium, such as a cannula or needle, in or on the insertion medium. Fluid attachment can be made to the fluid inlet port of the fluid conduit 12 of the. This can be particularly advantageous in applications involving penetration of relatively thick tissue, such as insertion through the human skull.

0033In addition to delivering drug-containing fluids, device 10 can also be used to deliver enzymes or other materials to alter tissue permeability and improve drug distribution within the target tissue. For example, penetration of drug-containing nanoparticles into brain tissue can be enhanced by enzymatic digestion of at least one extracellular matrix component and intracranial injection of nanoparticles into brain tissue. In another embodiment, at least one enzyme can be immobilized on the surface of the nanoparticles during the enzymatic digestion step. The device 10 may provide the ability to deliver enzymatic and / or other materials, as well as therapeutic substances, which may alter, for example, drug delivery sites, in virtually any order, sequencing and / or timing. It does not require the use of different delivery devices and does not involve the potential complexity of doing so.

0034The device 10 biopsies the tissue, for example, by passing the stylet or gripping tool through the fluid conduit 12 to the target site and then pulling the stylet or gripping tool containing the biopsy specimen from the target site. Can also be used to do. In some embodiments, the fluid conduit 12 may have a large diameter lumen extending through it for biopsy purposes, and a smaller fluid lumen is formed around the lumen. ..

0035The device 10 can be used to deliver the drug-containing fluid to the target tissue region under positive pressure. FIG. 4 shows an exemplary method of convection-enhanced delivery of a drug to a target tissue 40 in a patient's brain. After the site is properly prepared and washed, tissue openings can be formed through the patient's scalp and skull to expose the brain tissue 40. Before or after the formation of the tissue opening, a pedestal can optionally be attached to the patient to support the device 10 while the device 10 is inserted, which can be particularly useful in long-term implantation. ..

0036The device 10 can optionally be connected to a cannula (not shown) by a microfabrication interface for meshing with the device 10. Any of a variety of cannsulas can be used, including standard cannulas configured to connect with stereotactic frames in guided surgery. In some embodiments, the cannula may include a flexible catheter suitable for long-term (eg, 30 days) implantation. The catheter may be about 15 cm long and about 2 cm in diameter. The cannula may include a tubing portion approximately 1.83 m (approximately 6 feet) in length, with a connector at the proximal end for the fluid and biosensor interface.

0037The device 10 can advance into the brain tissue 40 through the tissue opening. As shown, the tissue receptive space 18 may be configured to compress or squeeze the tissue received into the tissue receptive space 18 as the device 10 advances through the tissue 40. The tissue compressed by the tissue receptive space 18 can form a seal that reduces the fluid drained from the outlet 20 of the fluid conduit 12 from regurgitating proximally across the tissue receptive space 18. Specifically, when the fluid discharged from the outlet 20 of the fluid conduit 12 flows back proximally between the outer surface of the fluid conduit 12 and the surrounding tissue 40, the fluid is compressed into the tissue receiving space 18. I come across 38 shoulders. Compression of tissue 38 against the wall of tissue receiving space 18 forms a seal that prevents fluid from flowing further proximally, thereby reducing unwanted backflow of infused fluid leaving the target area of tissue. Or it is prevented.

0038As mentioned above, device 10 may include a supporting scaffold that facilitates penetration of brain tissue towards the target area. One or more radiopaque markers may be included in device 10 to allow radiography (eg, to ensure that device 10 is properly placed inside or near the target tissue). it can. In embodiments where a degradable scaffold is used, the scaffold can be disassembled immediately after insertion, leaving only the fluid conduit 12 and the outer sheath 14. In some embodiments, the fluid conduit 12 and / or sheath 14 may be flexible so that the device 10 can move with the brain tissue 40 as the brain tissue 40 moves within the skull. This advantageously prevents the brain tissue adjacent to the device 10 from being locally deformed, which can occur in the rigid device. Such deformations can cause backflow of pressurized fluid along the surface of the device, unnecessarily preventing the fluid from reaching the target tissue.

0039Once the device 10 is positioned within or adjacent to the target tissue, the injected medium (eg, drug-containing fluid) can be fed to the device 10 through the fluid inlet port of the device 10 under positive pressure. The injected medium then flows through the fluid conduit 12 and is released under pressure from the outlet port 20 in the target area of the tissue. The delivery profile can be adjusted by varying parameters such as outlet port size, outlet port shape, fluid conduit size, fluid conduit shape, fluid supply pressure, fluid velocity, and the like. In some embodiments, the device 10 may be configured to deliver the fluid at a flow rate of about 5 μL / min to about 20 μL / min. In some embodiments, device 10 may be configured to deliver 50-100 μL per minute per channel so that each channel supports pressures above 689.48 kPa (100 psi). Can be configured.

0040In some embodiments, a gel or other material can be injected through device 10 to enhance tissue sealing prior to injecting the drug-containing fluid. For example, a seal gel can be injected through the device 10 and flow back along the outside of the device to fill and seal the voids that may exist between the device and the surrounding tissue, especially inside the tissue receiving recess 18. Exemplary sealing materials include cyanoacrylates, protein glues, tissue sealants, coagulative glues (eg, fibrin / thrombin / protein-based coagulant adhesives), and overall content. Includes materials such as those disclosed in US Patent Application Publication No. 2005/0277862 filed June 9, 2004 under the name "SPLITABLE TIP CATHETER WITH BIORESORBABLE ADHESIVE", which is incorporated herein by reference.

0041It is understood from the above that the methods and devices disclosed herein can result in convection-enhanced delivery of functional material directly to a patient's target tissue with little or no regurgitation. Will be done. This convection-enhanced delivery can be used to treat a wide range of diseases, health conditions, trauma, illnesses, and the like. As used herein, the term "drug" refers to any functional substance that can be delivered to a human or animal patient, including hormones, stem cells, gene therapies, chemicals, compounds. , Small and large molecules, dyes, antibodies, viruses, therapeutic agents and the like.

0042In some embodiments, the central nervous system (CNS) tumor is an antibody (eg, an anti-epidermal growth factor (EGF) receptor monoclonal antibody) or a nucleic acid construct (nucleic acid). It can be treated by delivering constructs (eg, ribonucleic acid interfering (RNAi) substances, antisense oligonucleotides, or adenoviruses, adeno-associated virus vectors, or other viral vectors) to the affected tissue. Epilepsy can be treated by delivering anticonvulsants to target areas in the brain. Parkinson's disease can be treated by delivering proteins such as glial cell-derived neurotrophic factor (GDNF) to the brain. Huntington's disease can be treated by delivering nucleic acid constructs such as ribonucleic acid interfering (RNAi) substances or antisense oligonucleotides to the brain. Neurotrophins can be delivered to the brain under positive pressure to treat stroke. Proteins such as lysosomal enzymes can be delivered to the brain to treat lysosomal storage diseases. Alzheimer's disease can be treated by delivering anti-amyloids and / or nerve growth factor (NGF) to the brain under positive pressure. Amyotrophic lateral sclerosis delivers proteins such as brain-derived neurotrophic factor (BDNF) or ciliary neurotrophic factor (CNTF) to the brain, spinal canal, or anywhere in the central nervous system under positive pressure. Can be treated by Chronic brain injury can be treated by delivering proteins such as brain-derived neurotrophic factor (BDNF) and / or fibroblast growth factor (FGF) to the brain under positive pressure.

0043It will be recognized that the use of the devices disclosed herein and the various therapeutic methods associated with them is not restricted to the patient's brain. Rather, these methods and devices can be used to deliver the drug to any part of the patient's body, including the spine. As a further embodiment, balance or hearing loss can be treated by injecting a drug-containing fluid directly into a portion of the patient's ear. One of a variety of drugs can be used to treat the ear, including the human atonal gene. The methods and devices disclosed herein can also be used to deliver therapeutic material (such as stem cells) to a foetation or a patient carrying a foetation. The methods and devices disclosed herein can be used to treat spongy malformations, for example by delivering one or more angiogenesis inhibitors to the spongy malformations.

0044One of the various therapies described herein delivers cofactors such as corticosteroids impregnated into the device, corticosteroids coated on the device, and / or growth-promoting enzymes to the target tissue. That can be further included. In addition, any of the various treatments described herein may further include long-term implantation of the device (eg, hours or days) to facilitate long-term treatment and therapy.

0045Some variants of device 10 are described below. Except as shown, the structures and operations of these variants are the same as in Device 10, so detailed description is omitted here for brevity.

0046In some embodiments, the device 10 may include multiple tissue receiving spaces 18. FIG. 5 shows an embodiment comprising a first tissue receiving space 18A and a second tissue receiving space 18B. As shown, a first outer sheath 14A is located above the fluid conduit 12 and defines a first tissue receiving space 18A. A second outer sheath 14B is placed on top of the first outer sheath 14A to define a second tissue receiving space 18B. Specifically, the second tissue receiving space 18B is formed between the outer surface of the first outer sheath 14A and the inner surface of the distal end 16B of the second outer sheath 14B. Two tissue receptive spaces are shown, but any number of tissue receptive spaces (eg, 3, 4, 5, or more) may be provided by adding an additional sheath layer. Will be recognized. A single sheath layer may provide multiple tissue receptive spaces, for example by forming a sheath layer with one or more stepped regions, each defining a tissue receptive space within. It can also be configured. Multi-stage devices such as those shown in Figure 5 devices) can provide an additional sealing area proximal to the most distal major sealing area. Providing any of these secondary and tertiary seal areas can enhance the primary seal or act as a backup in the event of a major seal failure.

0047As shown in FIGS. 6A-6C, the inner wall of the distal end 16 of the outer sheath 14 has the dimensions of the tissue receiving space 18 and the type of seal that results when the tissue is compressed within the tissue receiving space 18. , Can be molded to change. FIG. 6A shows a device 100 in which the inner surface of the distal end 116 of the sheath 114 has a concave curvature. FIG. 6B shows a device 200 in which the inner surface of the distal end 216 of the sheath 214 is conical. FIG. 6C shows a device 300 in which the inner surface of the distal end 316 of the sheath 314 has a convex curvature. These configurations can result in a sharper anterior edge at the periphery of the sheath compared to the cylindrical tissue receptive space 18 of device 10 and can also be compressed into the tissue receptive space or by the tissue receptive space. The amount of tissue that is tightened / pinned, as well as the degree of compression can be increased. Therefore, when the configurations of FIGS. 6A to 6C are used, a stronger seal can be obtained. However, note that even in the case of a cylindrical tissue receptive space, the anterior edge of the sheath can be sharpened to deflect the tissue into the tissue receptive space, thereby forming a better seal. I want to be. The size and shape of the tissue receiving space can be selected based on a variety of parameters, including the type of tissue into which the device should be inserted. In embodiments where there are multiple tissue receptive spaces, each tissue receptive space can have the same configuration (eg, all cylindrical, all conical, all convex, or all concave). Alternatively, one or more of the tissue receiving spaces may have different configurations. Thus, for example, one or more tissue receptive spaces may be cylindrical and one or more other tissue receptive spaces may be convex.

0048The tissue receiving recesses of the apparatus disclosed herein may include various surface features or treatments to enhance the seal formed between the apparatus and the surrounding tissue or gel. For example, the tissue receiving recesses may be coated with a biocompatible adhesive or may have a rough surface to form a tighter seal with the tissue or gel.

0049FIG. 7 shows an exemplary embodiment of the CED device 400, generally including a fluid conduit in the form of a microtip 412 and an outer sheath 414. The microtip 412 includes a substrate 442, which can be formed from a variety of materials, including silicon. The substrate 442 can have any of a variety of cross-sectional shapes, including a square or rectangular cross section as shown. One or more fluid channels 444 can be formed on the substrate 442. Fluid channel 444 may be formed from a variety of materials, including parylene. Further details regarding the structure, operation, and manufacture of micromachining tips, such as those shown in FIG. 7, are provided herein under the name "MULTI-DIRECTIONAL MICROFLUIDIC DRUG DELIVERY DEVICE", which is incorporated herein by reference in its entirety. It can be found in US Patent Application Publication No. 2013/0035560 filed on 1st May.

0050The outer sheath 414 can be coaxially arranged on the microtip 412 to form a tissue receiving space 418 between the outer sheath 414 and the microtip 412. In some embodiments, the microtip 412 may have a substantially rectangular outer cross section and the outer sheath 414 may have a substantially cylindrical inner cross section. In other embodiments, the microtip 412 and the outer sheath 414 may have a corresponding cross-sectional shape with a gap defined between them. The proximal end of the outer sheath 414 can be connected to catheter 446. Catheter 446 may be rigid or flexible, or may include rigid and flexible portions. A nose portion 448 (sometimes referred to herein as a "bullet-shaped nose" or "bullet-shaped nose portion") may be placed between the outer sheath 414 and the catheter 446, or the outer sheath 414 and the catheter. It may be placed on the junction with the 446. As shown, the nose portion 448 may be tapered from a small distal diameter corresponding to the outer diameter of the sheath 414 to a proximal enlargement corresponding to the outer diameter of the catheter 446. The tapered transition provided by the nose portion 448 can advantageously provide stress relief, which can act as a smooth transition from the sheath 414 to the catheter body 446, allowing the fluid to flow. This is to prevent uneven pressure on the surrounding tissue, which can create a backflow path. As shown, the nose portion 448 may be tapered in a conical shape, or may be tapered along a convex or concave curve. Various complex shapes can also be used, including conical, convex, and / or concave portions. The nose portion 448 can also be replaced by a blunt shoulder extending perpendicular to the longitudinal axis of the device 400. Any of a variety of taper angles can be used for the nose section 448. For example, the nose portion 448 is in the range of about 10 ° to about 90 ° with respect to the length axis of the device 400 and with respect to the length axis of the device. It can be tapered in the range of about 20 ° to about 70 ° and / or in the range of about 30 ° to about 50 ° with respect to the length axis of the device. For example, the nose portion 446 can be tapered at an angle of about 33 ° with respect to the longitudinal axis of the device 400. In some embodiments, additional sheaths can be provided, for example, as described above for FIG.

0051As shown in FIG. 8, catheter 446 may include a length mark or scale 450 to indicate the insertion depth of device 400. In some embodiments, the catheter 446 is acute stereotactic. It may be a straight, rigid catheter sized and configured for targeting). Catheter 446 can be formed from any of a variety of materials, including flexible materials, rigid materials, ceramics, plastics, polymer materials, PEEK, polyurethane, etc., and combinations thereof. In an exemplary embodiment, the catheter 446 has a length of about 10 cm to about 40 cm, for example about 25 cm. Catheter 446 may include one or more fluid lines extending through it. The fluid line can be defined by the catheter body itself, or by one or more inner sleeves or linings located inside the catheter body. Forming an inner sleeve or lining using any of a variety of materials, such as flexible materials, rigid materials, polyimides, Pevacs, PEEK, polyurethanes, silicones, fused silica tubes, etc., and combinations thereof. Can be done.

0052As shown in FIG. 9, one or more standard luer connectors or other connectors 452 are attached to the proximal end of catheter 446 for easy connection with the type of fluid delivery system shown in FIG. Can be. In the illustrated embodiment, the system 400 includes two connectors 452, which are for each of the two fluid channels formed in the catheter 446 and the microtip 412. However, it will be appreciated that any number of fluid channels and corresponding proximal catheter connectors may be provided. The system 400 may also include a collar 454 placed over the catheter 446 to set the desired insertion depth and act as a depth stop to prevent overinsertion. The collar 454 may slide in the longitudinal direction with respect to the catheter 446 and also has a thumbscrew 456 that engages the catheter to secure the collar in a longitudinal position fixed to the catheter. Can include. The system 400 may also include a tip protector 458 to prevent damage to the microtip 412 during insertion into the stereotactic frame fixture. An exemplary advanced protector is a US provisional patent application filed June 17, 2013 under the name "METHODS AND DEVICES FOR PROTECTING CATHETER TIPS", the entire contents of which are incorporated herein by reference. It is disclosed in the issue.

0053As shown in FIG. 10, system 400 may include one extension tube 460 to provide a fluid path between the proximal connector 452 of catheter 446 and the type of fluid delivery system shown in FIG. In the illustrated embodiment, a dual-channel peel-away extension. lines) 460 is illustrated. In an exemplary method using System 400, an incision can be formed in the patient and a catheter 446 is inserted through the incision to insert a target area of tissue (eg, a region of the patient's brain or central nervous system). ) Can be implanted. Catheter 446 can remain in the target area for minutes, hours, days, weeks, months, and so on. For the flexible catheter 446, the proximal end of the catheter can go under the patient's scalp and the proximal connector 452 extends from the incision. Catheter 446 can be inserted through the sheath to keep the catheter stiff and straight for stereotactic targeting. Alternatively, or in addition, a stylet can be inserted through the catheter to keep the catheter stiff and straight for stereotactic targeting. In some embodiments, the stylet may be inserted through an auxiliary lumen formed in the catheter, and the primary fluid delivery lumen may be infused with fluid during catheter insertion. Thus, in the case of catheters with first and second fluid lumens, a third lumen may be included to receive the stylet.

0054FIG. 11 is an enlarged view of an exemplary microtip 412. As shown, the microtip 412 generally includes a central body portion 462, with the first and second legs or tail 464 extending proximally from it, and the tip portion 466 extending distally from it. .. First and second microfluidic channels 444 are formed in or on the microtip 412, and those channels are distal tips along the proximal leg 464, across the central body portion 462. Part 466 extends. Each channel 444 may include one or more fluid inlet ports (eg, at the proximal end) and one or more fluid outlet ports (eg, at the distal end). As mentioned above, further details regarding the structure, operation, and manufacture of micromachining tips, such as those shown in FIG. 11, are incorporated herein by reference in their entirety, under the name "MULTIDIRECTIONAL MICROFLUIDIC DRUG DELIVERY DEVICE" 2012. It can be found in US Patent Application Publication No. 2013/0035560 filed on August 1, 2014.

0055The systems and methods for manufacturing and / or assembling the CED device 400 are shown in FIGS. 12-15. Generally speaking, after the microtip 412 is made, it is positioned in a molding or casting system, connecting one or more sheaths 414 to the microtip to form the nose portion 448. And / or the fluid line of the catheter 446 can be connected to the fluid channel 444 at the microtip.

0056FIG. 12 shows an exemplary embodiment of the molding system 500. System 500 includes a base plate 502 with a cradle 504 in which the proximal portion of catheter 446 is supported. The upper molded block 506 and the lower molded block 508 are connected to the base plate 502 by a clamp block 510 with one or more screws 512. The screws 512 may be tightened to lock the molding blocks 506, 508 in place during the injection process and may be removed so that the molding blocks can be opened to insert or remove components of the CED device. it can. The system 500 also includes an inlet port 514 through which the fluid material can be injected, pumped, etc. into the mold.

0057As shown in FIGS. 13-15, the lower molded block 508 includes a recess in which the lower half of the catheter body 446 can be located and a recess in which the lower half of the sheath 414 can be located. A molded cavity 516, which is substantially negative with the lower half of the nose portion 448, is formed between the recesses. These recesses can be sized so that the catheter body 446 and sheath 414 form a seal with the molding block 508 to prevent leakage of the fluid material injected into the molding cavity 516. One or more injection ports or channels 514 are formed in the molding block 508 to inject fluid material into the cavity 516. Although not shown, the upper molded block 506 is configured similar to the lower molded block 508, with a recess capable of receiving the upper half of the catheter body 446 and sheath 414, and substantially the upper half of the nose portion 448. It will be recognized that it comprises a molded cavity 516, which has opposite irregularities.

0058During use, the microtip 412 is such that the proximal leg 464 is located within each fluid line formed in the catheter body 446, and the distal tip 466 of the microtip is inside the sheath 414. It is positioned so that it is positioned inside the lumen. As mentioned above, in some embodiments, the catheter fluid line may be formed by an inner lining (eg, fused silica tube) placed within an outer housing (eg, ceramic housing) that defines the catheter body 446. .. The inner lining prevents leakage and can hold the catheter body 446 together if the outer housing is cracked or damaged. The microtip 412, catheter body 446, and sheath 414 are sandwiched between the upper molding block 506 and the lower molding block 508, and fluid material is injected through the molding channel 514 to the nose portion inside the molding cavity 516. A 448 is formed and the fluid line of the catheter 446 is connected to the fluid channel 444 at the microtip. Exemplary fluid materials include UV resins, polymers such as polyurethane, acrylics, PTFE, ePTFE, polyester and the like.

0059The fluid material can be injected at low speed to fill the cavity 516. In embodiments that use UV resin, the upper molded block 506 and the lower molded block 508 can be made of a transparent material so that the UV resin can be cured with UV light. When the UV resin is injected into the micromolded cavity 516, the UV resin wicks / flows above the tail 464 of the microtip and below the fluid line located above the tail. up) You can start. Once the resin has flowed into the fluid line, it can be illuminated with UV light to "solidify" the resin in place and prevent it from escaping / flowing excessively (and on the tail 464 and the tip of the tail). Do not completely enclose the entrance hole of). After the material has hardened, the molding blocks 506, 508 may be separated and the CED device 400 may be removed from the molding system 500.

0060It will be appreciated that the systems and methods described above may be modified in several ways without departing from the scope of the present disclosure. For example, the molding process may only be used to connect the fluid lines, and the bullet-shaped nose portion may be formed using a different process once the fluid connection has been made. Also, as the mechanism by which fluid line couplings are formed, wicking has been described herein, but these couplings may be controlled by filling pressure, timing, and other molding variables. Will be recognized. The bullet-shaped nose can be overmolded directly onto the microtips. Although exemplary microtips and exemplary catheter bodies are illustrated, the micromolding methods and devices disclosed herein can be used with any of a variety of tips and / or catheters. Will be recognized.

0061Alternative systems and methods for manufacturing and / or assembling the CED device 400 are shown in FIGS. 16-21. As shown in FIGS. 16-19, the bullet nose and one or more sheaths or overtubes can be assembled separately using the overmolding process as described below to make the molding 470. .. To assemble the system 400, the proximal leg 464 of the microtip 412 is located at the distal end of the catheter body 446 (eg, by inserting each leg into each lining located inside the outer catheter housing). It is inserted in the part. A fluid material (eg, an adhesive such as a UV curable adhesive) is then applied to the legs 464 to connect the fluid channels of each leg to the corresponding fluid lines of the catheter body 446. Can be done. The molding portion 470 can then slide over the distal end of the micro tip 412, and the central body portion 462 of the micro tip is located inside the hollow of the molding and the tip of the micro tip. The portion 466 extends through the molding and projects from its distal end.

0062The molding 470 may include a shoulder, which defines a proximal male portion 472 that meshes within a female countersunk hole 474 formed in the distal tip of the catheter body 446. Alternatively, the catheter body 446 may demarcate the male portion and the molded portion 470 may include a female countersunk hole. Catheter body 446 to mold 470, including threaded interfaces, snap-fit interfaces, key-slot interfaces, or any other interlock interface that provides alignment and / or overlap between the molding and the catheter body. It will also be appreciated that other methods of meshing may be used. In some embodiments, the countersunk hole 474 can be formed by machining a recess within the distal end of the ceramic catheter body 446. The inner lining of the catheter may then be inserted into the outer housing of the ceramic, the end of the inner lining being flush with the bottom of the countersunk hole 474. The molding 470 may be attached to the catheter body 446 using a fluid material (eg, UV adhesive), which fluid material is placed in the countersunk holes 474 and / or the male portion 472 before assembling the components. It may be applied, or after the components have been assembled or dry-fitted, it may be applied through one or more openings 476 formed in the sidewalls of the molding. The fluid material can be cured to form a seal between the fluid lines and to secure the components of the CED device 400 to each other.

0063An exemplary overmolding system 600 for forming a bullet-shaped nose and connecting the bullet-shaped nose to one or more overtubes to form a molding section 470 is shown in FIG. The mold system 600 includes an upper plate 602 and a lower plate 604, which sandwich one or more overtubes, both defining one having an unevenness opposite to the bullet-shaped nose. Plates 602, 604 also define a plug for forming a bullet-shaped nose as a hollow structure that can be filled later as described above during final assembly. The fluid material can be injected through injection ports 606 formed in plates 602, 604 using a syringe or pump to form a hollow bullet-shaped nose over one or more overtubes. In some embodiments, the fluid material is a hot resin injected under pressure, forming a strong hold with the overtube upon curing. The overtube can be formed from any of a variety of materials, including fused silica tubing.

0064An enlarged scale view of an exemplary molded portion 470 is shown in FIG. 21 with typical dimensions. Any of the nose portions and / or sheaths described herein may be formed with the same or similar external dimensions. Unless otherwise indicated, the dimensions shown in FIG. 21 are shown in inches.

0065Figures 22-23 were performed by injecting dye into a gel designed to mimic tissue through a CED device of the type described herein, which has first and second fluid channels. , Shows exemplary results of a gel study. As shown in FIG. 22, at flow rates of 5, 10, and 12 μL / min (the sum of the flow rates of both channels combined), little or no backflow occurs. As shown in FIG. 23, a flow rate of 5 μL / min resulted in a uniform distribution of dyes over time with little or no backflow.

0066FIGS. 24-29 are exemplary animal studies performed using an in vivo porcine model infused into multiple anatomical structures using a CED device of the type described herein. The result is shown. At much faster flow rates than typical clinical flow rates for CED, little or no regurgitation along the catheter path was observed. This study demonstrated the ability to inject small, medium, and large molecules using the types of CED devices disclosed herein, and confirmed the functionality of independent flow channels. During the multi-hour acute infusion for several hours, there was no air bubble obstruction or introduction. The device was found to be compatible with magnetic resonance imaging and other stereotactic surgical procedures. No leaks, broken attachments, or other catheter problems were observed.

0067When inserted into the porcine brain, as shown in FIG. 24, the ceramic catheter body and bullet-shaped nose appear as thick black lines in magnetic resonance (MR) images. The injected gadolinium (Gd) looks like a bright cloud in the MR image. Due to its small size, the minute tip cannot be easily seen in MR images.

0068FIG. 25 illustrates a series of MR images showing gadolinium injection into the white matter of porcine brain at a flow rate of 1, 3, 5, 10, 20 μL / min. As shown, there is no regurgitation of the injectate along the path of the ceramic catheter shaft. If the infusion cloud becomes too large, the infusion will overflow into the surrounding anatomy rather than regurgitate along the path of the catheter, and the system will reduce or prevent regurgitation. Ability is emphasized. A maximum flow rate of 20 μL / min is shown, but it is expected that similar results will be obtained at a flow rate of 30 μL / min or higher. Such high flow rates could not be tested during animal studies because the subject's brain was filled with gadolinium.

0069FIG. 26 illustrates a series of MR images showing gadolinium injection into the thalamus of the porcine brain at a flow rate of 1, 3, 5, 10, 20 μL / min. As shown, there is no regurgitation of the injectate along the path of the ceramic catheter shaft. At about 20 μL / min there is a slight backflow across the bullet nose, which is significantly faster than the typical clinical CED flow rate (approximately 5 μL / min).

0070FIG. 27 illustrates a series of MR images showing gadolinium injection into the putamen of the porcine brain at a flow rate of 1, 2, 5, 10, 15 μL / min. As shown, there is no backflow of the infusion along the path of the ceramic catheter shaft, as the infusion remained spherical throughout the ramped infusion.

0071The regurgitation studies described above show that regurgitation along the catheter shaft is minimal at high flow rates (maximum 20 μL / min for white matter, 5-20 μL / min for thalamus, 5-15 μL / min for putamen). Was done. These flow rates are much faster than typical clinical CED flow rates (eg, about 5 μL / min). In addition to being based on the MR images contained herein, 3D analysis of the infusion was used to determine if reflux had occurred. No regurgitation was observed in a total of 11 injections made in various anatomical structures.

0072FIG. 28 illustrates a series of MR images showing gadolinium injected into the white matter of porcine brain at a flow rate of 5 μL / min after injection periods of 1, 9, 16, 24, and 50 minutes. The lower set of images contains overlapping distributions. As shown, a uniform distribution without regurgitation is observed even with long injections and when large amounts of infusion are delivered. Similar results were observed when injected into the thalamus and putamen of the porcine brain.

0073In Figure 29, a CED device of the type described herein simultaneously delivers galbumin (a gadolinium-labeled albumin mixed with europium) through a first fluid channel and an IVIS dye through a second fluid channel. MR and in vivo imaging system (IVIS) images of the thalamus of the pig brain when used for infusion are shown. As shown, two different injections were successfully injected from two independent channels. The uniform distribution of the two injections indicates that they were mixed at the tip outlet as desired. No evidence of subarachnoid leakage was observed. This indicates that the system can be used to deliver Gd tracers and drugs or other molecules, as well as to observe Gd tracers under MR to observe the distribution of drugs or other molecules.

007430-31 show a comparison of measurements taken with a CED device of the type described herein with simulated measurements of a conventional 0.3 mm catheter. As shown in FIG. 30, in the type of CED apparatus described herein, the concentration of injected colloidal Gd in the white matter is more uniform than in conventional 0.3 mm catheters. As shown in FIG. 31, when using a CED device of the type described herein, extracellular expansion of white matter tissue is restricted to the tip area by a bullet-shaped nose and tube steps, thereby limiting it to the tip area. , Prevent backflow along the path of the catheter. On the other hand, in a conventional 0.3 mm catheter, the injection pressure increases the extracellular dilation that occurs along the path of the catheter, resulting in regurgitation.

0075The injection study described above showed that 150 μL of infusion could be delivered into the white matter and thalamus without regurgitation along the path of the catheter. The study also showed that the concentration profile of the injectate distribution within the tissue was within the typical range of intraparenchymal drug delivery. It was also proved that the injection of colloidal Gd (large molecule of 30 to 50 nm) was successful.

0076The devices disclosed herein can be manufactured using any of a variety of techniques. For example, the device can be assembled by stacking multiple tubes on top of each other, micromachining the multiple tubes, and molding a step or nose feature that accommodates the tissue receiving space on the fluid conduit. Alternatively, it can be manufactured by building one or more parts of the device on a substrate using a lithography micromachining process.

0077Further details regarding CED methods and devices, as well as related manufacturing techniques, exemplary microtips, and exemplary catheters are disclosed in the following references, the entire contents of each of which are described herein by reference. Incorporated into the book: US Patent Application Publication No. 2013/0035560 filed on August 1, 2012 under the name "MULTIDIRECTIONAL MICROFLUIDIC DRUG DELIVERY DEVICE"; US Patent Application Publication No. 2013/0035574 filed on August 1, 2012 under the name "MICROFLUIDIC DRUG DELIVERY DEVICES WITH VENTURI EFFECT"; US Patent Application Publication No. 2013/0035660 filed on August 1, 2012 under the name "MULTIDIRECTIONAL MICROFLUIDIC DRUG DELIVERY DEVICES WITH CONFORMABLE BALLOONS"; US Provisional Patent Application No. 61 / 835,905 filed on June 17, 2013 under the name "METHODS AND DEVICES FOR PROTECTING CATHETER TIPS"; US Provisional Patent Application No. 61 / 860,402 filed on July 31, 2013 under the name "DRUG DELIVERY SYSTEMS"; US Patent Application Publication No. 2010/0098767 filed on July 31, 2009 under the name "CONVECTION ENHANCED DELIVERY APPARATUS, METHOD, AND APPLICATION"; US Patent Application Publication No. 2013/0046230 filed on November 7, 2012 under the name "ULTRA SOUND-ASSISTED CONVECTION ENHANCED DELIVERY OF COMPOUNDS IN VIVO WITH A TRANSDUCER CANNULA ASSEMBLY".

0078Although the present invention has been described with reference to specific embodiments, it should be understood that many modifications can be made within the spirit and scope of the described concept of the invention. Therefore, the present invention is not limited to the described embodiments, and is intended to have all the scope defined by the wording of the claims.

0079[Implementation mode] (1) In a convection enhanced delivery (CED) device A microtip having at least one fluid channel extending along the proximal part, the central part, the distal part, and the proximal part, the central part, and the distal part, said at least one fluid channel. A microtip with an outlet port at its distal end and an inlet port at its proximal end, A first outer sheath coaxially arranged on the distal portion of the microtip, the distal portion of the microtip protruding from the distal end of the first outer sheath. With the first outer sheath, A first tissue receiving space defined between the outer surface of the microtip and the inner surface of the distal end of the first outer sheath. A catheter body that extends proximally from the microtip, wherein at least one fluid channel of the microtip communicates fluidly with the respective inner lumen of the catheter body. A nose portion that is arranged on at least the central portion of the micro tip portion and extends between the first outer sheath and the catheter body, and the nose portion is the outer diameter of the first outer sheath. A nose portion that defines a tapered outer surface from a distal small diameter corresponding to the catheter body to a proximal enlargement corresponding to the outer diameter of the catheter body. Including equipment. (2) In the apparatus according to the first embodiment. The tissue receptive space is a device configured to compress the tissue received within the tissue receptive space as the device advances through the tissue. (3) In the apparatus according to the second embodiment. The tissue compressed by the tissue receptive space forms a seal that reduces the fluid drained from the outlet port of the at least one fluid channel proximally regurgitating across the tissue receptive space. .. (4) In the apparatus according to the first embodiment. It further comprises a second outer sheath placed on top of the first outer sheath, the second tissue receiving space being the outer surface of the first outer sheath and the distal end of the second outer sheath. A device defined between the inner surface of the device. (5) In the apparatus according to the first embodiment. The inner surface of the distal end of the first outer sheath is shaped to compress the tissue received within the inner surface as the device advances through the tissue. ..

0080(6) In the apparatus according to the fifth embodiment. A device in which the inner surface of the distal end of the first outer sheath is conical. (7) In the apparatus according to the fifth embodiment. A device in which the inner surface of the distal end of the first outer sheath is convex. (8) In the apparatus according to the fifth embodiment. A device in which the inner surface of the distal end of the first outer sheath is concave. (9) In the apparatus according to the first embodiment. An apparatus in which the inner diameter of the distal end of the first outer sheath is about 1 μm to about 200 μm larger than the outer diameter of the distal portion of the microtip. (10) In the apparatus according to the first embodiment. An apparatus in which the inner diameter of the distal end of the first outer sheath is about 10% to about 100% larger than the outer diameter of the distal portion of the microtip.

0081(11) In the apparatus according to the first embodiment. The first outer sheath is a device having a circular outer cross section. (12) In the apparatus according to the first embodiment. An apparatus in which the at least one fluid channel is formed from at least one of a parylene composition, a silastic composition, a polyurethane composition, and a PTFE composition. (13) In the apparatus according to the first embodiment. A device further comprising a fluid reservoir that communicates with the inner lumen of the catheter body and is configured to supply fluid to the inner lumen under positive pressure. (14) In the apparatus according to the first embodiment. The device, wherein the microtip is flexible. (15) In the apparatus according to the first embodiment. The microtip is a device that includes an embedded microsensor.

0082(16) In the apparatus according to the fifteenth embodiment. The embedded microsensor comprises at least one of a queryable sensor, a pressure sensor, a glutamate sensor, a pH sensor, a temperature sensor, an ion concentration sensor, a carbon dioxide sensor, an oxygen sensor, and a lactate sensor. (17) In the apparatus according to the first embodiment. A device having a non-traumatic shape, wherein the distal end of the microtip is configured to penetrate tissue without causing trauma. (18) In the apparatus according to the first embodiment. The microtip is a device that contains a certain amount of drug, is coated with a drug, or is impregnated with a drug. (19) In the apparatus according to the eighteenth embodiment. A device comprising the agent, an antibacterial agent, an anti-inflammatory agent, a corticosteroid, and at least one of dexamethasone. (20) In the apparatus according to the first embodiment. The microtip portion is an apparatus including a substrate on which the at least one fluid channel is formed.

0083(21) In the apparatus according to the 20th embodiment. The substrate is an apparatus having a rectangular cross section. (22) In the apparatus according to the first embodiment. A device in which the catheter body is formed of a rigid material and each inner lumen of the catheter body is defined by a sleeve formed of a flexible material. (23) In the apparatus according to the 22nd embodiment. The catheter body is made of at least one of ceramic, PEEK, and polyurethane. A device in which each sleeve is formed from at least one of polyimide, pevacs, PEEK, polyurethane, silicone, and fused silica. (24) In the apparatus according to the first embodiment. The catheter body is a device made of a flexible material. (25) In the method of assembling the apparatus according to the first embodiment. Forming the nose portion by molding the nose portion on the first outer sheath, Inserting the minute tip into the proximal end of the nose Connecting the proximal portion of the microtip to the catheter body and A fluid material is injected through an inlet port formed in the nose portion to fill the inside of the nose portion, and the microtip portion and the catheter body are fixed to the nose portion. Including methods.

0084(26) In a convection enhanced delivery (CED) device A fluid conduit with proximal and distal ends, A first outer sheath coaxially arranged over the fluid conduit, wherein the fluid conduit extends from the distal end of the first outer sheath, and a first outer sheath. A first tissue receiving space defined between the outer surface of the fluid conduit and the inner surface of the distal end of the first outer sheath. Including equipment. (27) In the micro molding device A molded cavity sized and configured to receive the catheter body and the catheter microtip inside, at least one fluid channel of the microtip inside the corresponding fluid line of the catheter body. Molded cavities and One or more molding channels, through which the molding fluid is injected to fill the molding cavity, the microtip can be fixed to the catheter body, and the microtip can be fixed. The at least one fluid channel comprises one or more molded channels that communicate with the at least one fluid line in the catheter body. Including equipment. (28) In the apparatus according to the 27th embodiment. The device is transparent so that UV light can pass through the device in order to cure the molding fluid arranged inside the molding cavity. (29) In the apparatus according to the 27th embodiment. An apparatus in which the molded cavity is sized and configured to form a bullet-shaped nose portion above the microtip and at least a portion of the outer sheath received within the molded cavity. (30) In the method of delivering a therapeutic agent to a patient A first outer sheath advances a fluid conduit around it into the tissue and is defined between the outer surface of the fluid conduit and the inner surface of the distal end of the first outer sheath. Compressing tissue into one tissue receptive space, Delivering the fluid containing the therapeutic agent under positive pressure through the fluid conduit into a portion of the tissue adjacent to the distal end of the fluid conduit. Including methods.

0085(31) In the method described in embodiment 30, A method further comprising delivering a seal gel through the fluid conduit prior to delivering the fluid containing the therapeutic agent to fill one or more gaps existing between the fluid conduit and the tissue. (32) In the method described in embodiment 30, The tissue compressed into the first tissue receiving space forms a seal that reduces the fluid drained from the distal end of the fluid conduit to flow proximally across the tissue receiving space. ,Method. (33) In the method described in embodiment 30, Further comprising advancing the second outer sheath disposed over the first outer sheath into the tissue, the tissue is the outer surface of the first outer sheath and distal to the second outer sheath. A method of being compressed into a second tissue receiving space defined between the inner surface of the end. (34) In the method described in embodiment 30, The method, wherein the inner surface of the distal end of the first outer sheath is at least one of conical, convex, and concave. (35) In the method described in embodiment 30, A method further comprising controlling the delivery of fluid through the fluid conduit based on the output of a microsensor embedded in the fluid conduit.

0086(36) In the method described in embodiment 30, The methods include central nervous system (CNS) tumors, intractable epilepsy, Parkinson's disease, Huntington's disease, stroke, lithosome accumulation, chronic brain injury, Alzheimer's disease, muscular atrophic lateral sclerosis, balance disorders, hearing disorders, and sponges. A method used to treat at least one disease selected from malformations. (37) In the method according to embodiment 30 Advancing the fluid conduit involves bringing the nose portion into contact with the tissue, the nose portion extending between the first outer sheath and the proximal catheter body, and the nose portion being the first. A method of tapering from a small distal diameter corresponding to the outer diameter of the outer sheath to a proximal enlargement corresponding to the outer diameter of the catheter body. (38) In the method described in embodiment 30, The fluid conduit is connected to the distal end of the flexible catheter and The method is Inserting the catheter through the incision and Positioning the fluid duct near the portion of the tissue using stereotactic targeting, Removing the stylet inserted through the catheter and Giving the proximal end of the catheter under the patient's scalp Connecting one or more proximal fluid connectors of the catheter to a fluid delivery system Including further, methods.

0087<figref num="1">It is a perspective view of one exemplary embodiment of a CED apparatus.</figref><figref num="2">It is sectional drawing of the device of FIG. 1 taken in the plane perpendicular to the length direction axis of a device.</figref><figref num="3">FIG. 5 is a schematic diagram of a fluid delivery system including the device of FIG.</figref><figref num="4">It is a schematic view of the device of FIG. 1 inserted into a tissue.</figref><figref num="5">It is a perspective view of another exemplary embodiment of a CED apparatus.</figref><figref num="6A">FIG. 5 is a plan view of another exemplary embodiment of the CED apparatus.</figref><figref num="6B">FIG. 5 is a plan view of another exemplary embodiment of the CED apparatus.</figref><figref num="6C">FIG. 5 is a plan view of another exemplary embodiment of the CED apparatus.</figref><figref num="7">It is a perspective view of another exemplary embodiment of a CED apparatus.</figref><figref num="8">It is another perspective view of the CED apparatus of FIG.</figref><figref num="9">FIG. 6 is a perspective view of the CED device of FIG. 7 provided with a depth stop and a tip protector.</figref><figref num="10">FIG. 7 is a plan view of the CED device of FIG. 7 with one extension tube.</figref><figref num="11">It is a perspective view of the minute tip part of the CED apparatus of FIG.</figref><figref num="12">It is a perspective view of an exemplary embodiment of a molding system.</figref><figref num="13">It is a perspective view of the CED apparatus of FIG. 7 manufactured by using the molding system of FIG.</figref><figref num="14">It is a top view of the CED apparatus of FIG. 7 manufactured using the molding system of FIG.</figref><figref num="15">It is another perspective view of the CED apparatus of FIG. 7 manufactured using the molding system of FIG.</figref><figref num="16">It is a partial decomposition sectional perspective view of another exemplary embodiment of a CED apparatus.</figref><figref num="17">It is a partial decomposition perspective view of the CED apparatus of FIG.</figref><figref num="18">It is a perspective view of the CED apparatus of FIG.</figref><figref num="19">It is a map of the molding filling time of the nose part of the CED apparatus of FIG.</figref><figref num="20">FIG. 6 is a perspective view of an exemplary embodiment of a molding system for forming the nose portion of the CED device of FIG.</figref><figref num="21">FIG. 6 is a scaled-up view of an exemplary embodiment of the nose portion of the CED device of FIG.</figref><figref num="22">A series of images showing a dye injected using a CED device into a gel designed to mimic tissue.</figref><figref num="23">Another series of images showing the dye being injected using a CED device into a gel designed to mimic tissue.</figref><figref num="24">Magnetic resonance imaging of a pig's brain with a CED device inserted and gadolinium dye injected.</figref><figref num="25">A series of magnetic resonance imaging showing gadolinium injected into the white matter of porcine brain at a flow rate of 1, 3, 5, 10, 20 μL / min using a CED device.</figref><figref num="26">A series of magnetic resonance imaging showing gadolinium injected into the thalamus of the porcine brain at a flow rate of 1, 3, 5, 10, 20 μL / min using a CED device.</figref><figref num="27">A series of magnetic resonance imaging showing gadolinium injected into the putamen of the porcine brain at a flow rate of 1, 2, 5, 10, 15 μL / min using a CED device.</figref><figref num="28">A series of magnetic resonance imaging showing gadolinium injected into the white matter of porcine brain at a flow rate of 5 μL / min using a CED device after injection times of 1, 9, 16, 24, and 50 minutes.</figref><figref num="29">Magnetic resonance imaging and in vivo imaging system images of the thalamus of the porcine brain when a CED device was used to inject galbumin and IVIS dyes simultaneously.</figref><figref num="30">This is a comparison between the concentration of the injectable solution using the CED device of the type described in the present specification and the concentration of the simulated injectable solution using a conventional catheter.</figref><figref num="31">This is a comparison between tissue enlargement using the type of CED apparatus described herein and simulated tissue enlargement using a conventional catheter.</figref>