Patent Publication Number: US-2021162173-A1

Title: Fluid delivery systems and methods

Description:
This application is a continuation of U.S. patent application Ser. No. 16/113,955, filed Aug. 27, 2018, which is hereby incorporated by reference herein in its entirety. 
    
    
     FIELD OF THE DISCLOSURE 
     The present disclosure generally relates to fluid delivery systems and, more particularly, to intrathecal fluid delivery systems. 
     BACKGROUND 
     Intrathecal administration is a valuable tool for introducing therapeutic agents into the cerebral spinal fluid (CSF), which allows distribution throughout the central nervous system. Indeed, therapeutics administered to CSF are distributed to the brain and spinal cord, thereby avoiding potential delivery issues through the blood-brain barrier. Most drugs delivered to the CSF require multiple administrations, requiring at least periodic access to the intrathecal space over the course of a treatment regimen. Some individuals are unable to receive medication via lumbar puncture due to anatomical barriers, such as spinal deformities, and/or surgical interventions, such as implantation of stabilizing rods and spondylosis. Bone fusions, sharp angles, and instrumentation in these individuals complicate or prevent direct lumbar puncture entry into the intrathecal space because there is no space between the bones to allow safe puncture of the dura. In these patients, extraordinary means are often required to achieve intrathecal access; for example, an oscillating drill may be required to bore through the bone mass or a laminectomy procedure may be required, which heightens the risk associated with intrathecal administration. There remains a need in the art for a delivery system that allows repeated administration of substances to the intrathecal space. 
     SUMMARY 
     In accordance with one aspect, a fluid delivery system is disclosed that includes a port that is implantable to a subcutaneous location. The port includes a body that defines a chamber having an open top and a delivery opening and a septum coupled to the body to extend over the open top of the chamber. The fluid delivery system further includes an intrathecal catheter that has a proximal end that is configured to be coupled to the port and fluidly coupled to the delivery opening of the chamber, a distal end, a central passage extending between the proximal end and the distal end, and a distal outlet in the distal end. The fluid delivery system further includes a plug that has a body with a passage to receive the intrathecal catheter therethrough, where the plug is configured to be inserted into the fascia to protect against leakage of cerebrospinal fluid. 
     According to some forms, that fluid delivery system can include one or more of the following aspects: the intrathecal catheter can include a plurality of radially oriented outlets, where the plurality of radially oriented outlets can be disposed along an axial length of the intrathecal catheter in a spiral configuration, the plurality of radially oriented outlets can include at least one of: one or more rings of outlets disposed within a plane normal to an axial length of the intrathecal catheter or a plurality of outlets aligned and spaced from one another along the axial length of the intrathecal catheter. 
     According to some forms, the fluid delivery system can include one or more of the following aspects: the intrathecal catheter can be radiopaque; the intrathecal catheter can include radiopaque markings at one or more of: adjacent to the distal end, above a start of the plurality of radially oriented outlets, or below an end of the radially oriented outlets; at least a portion of the intrathecal catheter can have a 3 layer construction including an inner lumen, a reinforcement layer, and an outer jacket; the distal end of the intrathecal catheter can include an atraumatic tip allowing implantation without damaging or exiting the intrathecal space; the central passage can include a choked portion adjacent to the distal outlet to create a venturi effect with fluid being dispensed through the distal outlet; the distal end of the intrathecal catheter can include one or more side passages that fluidly couple the central passage to an exterior of the intrathecal catheter to draw in fluid from the exterior of the intrathecal catheter and provide flow mass amplification to fluid being dispensed through the distal outlet; the distal outlet can have a smaller diameter than an inner diameter of the central passage of the intrathecal catheter adjacent to the distal outlet; the central passage can have an increased inner diameter portion in the distal end of the intrathecal catheter relative to an intermediate portion of the central passage, where the increased inner diameter portion extends to the distal outlet; the intrathecal catheter can have an outer diameter in the range of about 0.25 mm to about 1.5 mm; the intrathecal catheter can include an outwardly tapered portion adjacent to the proximal end thereof, where the outwardly tapered portion is configured to engage the dura over the catheter opening therein; the proximal end of the intrathecal catheter can include a reinforcement material increasing the hoop strength of the proximal end, where the reinforcement material includes one or more of: a plurality of rings embedded within the intrathecal catheter proximal end, a coil embedded within the intrathecal catheter proximal end, a polymer tube embedded within the intrathecal catheter proximal end, or a braided material embedded within the intrathecal catheter proximal end. 
     In accordance with a second aspect, a method of delivering an agent to a patient that has undergone a spinal stabilization or fusion procedure or suffers from a spinal deformity is disclosed that includes implanting a fluid delivery system in the patient such that a catheter of the fluid delivery system is disposed within the patient&#39;s intrathecal space, the catheter characterized by a catheter body having an outer diameter in the range of about 0.25 mm to 1.5 mm and a composite, kink-resistant structure, and the fluid delivery system further comprising a plug having a body with a passage to receive the catheter body therethrough, the plug configured to be inserted into the fascia to protect against leakage of cerebrospinal fluid; and releasing the agent via the catheter into the intrathecal space. 
     In accordance with a third aspect, a method of treating a disorder selected from the group consisting of Huntington&#39;s disease, Spinal Muscular Atrophy (SMA), survival motor neuron (SMN) deficiency, amyotrophic lateral sclerosis (ALS), Angelman&#39;s Syndrome, Dravet Syndrome, Alzheimer&#39;s disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson&#39;s Disease, central nervous system (CNS) lymphoma, and Leptomeningeal Cancer in a patient in need thereof is disclosed that includes implanting a fluid delivery system in the patient such that a catheter of the fluid delivery system is disposed within the patient&#39;s intrathecal space, the catheter characterized by a catheter body having an outer diameter in the range of about 0.25 mm to 1.5 mm and a composite, kink-resistant structure, and the fluid delivery system further comprising a plug having a body with a passage to receive the catheter body therethrough, the plug configured to be inserted into the fascia to protect against leakage of cerebrospinal fluid; and releasing a therapeutic agent via the catheter into the intrathecal space such that the disorder is treated. 
     In accordance with a third aspect, a fluid delivery system is disclosed that includes a port implantable to a subcutaneous location. A body of the port defines a chamber having an open top and a delivery opening, a septum of the port is disposed on the body and includes a lower surface that extends over the open top of the chamber and an opposite, upper surface, and a cap of the port defines an opening extending therethrough. The cap is configured to be coupled to the body to secure the septum within the port with the opening providing needle access to the septum and the cap includes a downwardly tapered surface extending around the opening and configured to direct a needle towards the upper surface of the septum. The fluid delivery system further includes a catheter connection portion of the body. 
     In accordance with a fourth aspect, a fluid delivery system is described that includes a port that is implantable to a subcutaneous location secured to a bony structure of a patient. A body of the port defines a chamber that has an open top and a delivery opening, a septum of the port is disposed on the body to extend over the open top of the chamber, and a cap of the port is configured to be coupled to the body to secure the septum within the port. The cap defines an opening extending therethrough, such that with the cap coupled to the body, the opening provides needle access to the septum. 
     According to some forms, the above fluid delivery systems can include one or more of the following features: one or more of the body, septum, cap, or catheter can be radiopaque; the cap can include a downwardly tapered surface extending around the opening; the port can include raised protrusions that are configured to provide palpatory feedback; the port can include outwardly protruding suture plugs that are configured to provide palpatory feedback; the port can include a raised lip that extends around the septum, and that system can include a guide tool that has a profile that is configured to mate with the raised lip through tissue to provide an external location detector for the septum; the port can include an actuator having a movable portion to provide at least one of tactile or visual feedback in response to actuation; piezoelectric crystals that are mounted to the port and configured to vibrate in response to an electric field introduced by an external instrument and, optionally, one or more LEDs mounted to the port and electrically coupled to the piezoelectric crystals to energize in response to palpation of the piezoelectric crystals; one or more magnets distributed about the septum within the port, and the system can include a metallic external guide that is attracted to the one or more magnets through tissue to provide a guide for needle access to the septum; the port can include metallic portions that are distributed about the septum, and that system can include a magnetic ring that is configured to magnetically couple to the metallic portions through tissue to provide a guide for needle access to the septum; the body and cap can include a combination of metallic and non-metallic components such that the body and cap are distinguishable under imaging; a plurality of LEDs mounted to the port to provide illumination through tissue of at least one of the septum or around the septum; one or more sensors disposed within the port to provide one or more of: distance, alignment, orientation, targeting, or location data relative to an external device in communication with the one or more sensors; the septum can include one or more internal cavities filled with an aqueous gel material detectable by ultrasound; the body can include a side opening to the chamber for a stylet and the system can further include a septum mounted within the side opening; or a therapeutic dose impregnated or pre-loaded in the port. 
     According to additional forms, the fluid delivery system can further include a catheter that has a proximal end configured to be coupled to the body to be fluidly coupled to the delivery opening of the chamber and a distal end having an outlet. According to further forms, the catheter can include radially oriented outlets disposed along a length thereof in a spiral configuration; the catheter can include radiopaque markings at one or more of: adjacent to the distal tip, above a start of the spiral configuration, below an end of the spiral configuration; the catheter can have a 3 layer construction including an inner lumen, a reinforcement layer, and an outer jacket; the distal end of the catheter can include an atraumatic tip; or the distal end of the catheter can include side passages for flow mass amplification. 
     According to further forms, a catheter can be coupled to the port by any of the following: the delivery opening can include a cylindrical cavity having a connection portion, which can be one of a threaded portion, a snap-fit recess, or a luer lock recess, and the system can include a gasket disposed over the catheter proximal end and a fastener configured to engage the connection portion of the cylindrical cavity to compress the compression member to secure the catheter proximal end within the cylindrical cavity; the port can include an outlet tube extending from the delivery opening of the chamber, the catheter proximal end can have an annular configuration sized to have the outlet tube inserted therein and the system can further include a compression member, which can be one of a compression spring, a compression fitting, or an o-ring, disposed around the catheter proximal end and outlet tube to secure the catheter to the port; the port can include an outlet tube extending from the delivery opening of the chamber, the catheter proximal end and the outlet tube can have a lap joint connection, and the system can further include a clamping member disposed over the lap joint connection to create fluid tight seal. 
     According to any of the above forms, the fluid delivery system can further include one or more dosages of a therapeutic agent, as described further below. 
     In accordance with a fifth aspect, a method for implanting a fluid delivery port and a catheter in an intrathecal space of a patient is described herein that includes mounting the port to a bony structure within a subcutaneous space of the patient, disposing a distal tip of the catheter in the intrathecal space, tunneling a proximal end of the catheter under the skin of the patient to the port, and connecting the proximal end of the catheter to the port. 
     According to some forms, connecting the proximal end of the catheter to the port can include inserting the proximal end of the catheter into an annular gasket, inserting the proximal end of the catheter and the compression member into a cylindrical outlet cavity of the port, and inserting a fastener into the cylindrical outlet cavity of the port to longitudinally compress the gasket and secure the proximal end of the catheter to the port. 
     According to other forms, connecting the proximal end of the catheter to the port can include disposing the proximal end of the catheter over an outlet tube of the port and securing the catheter to the outlet tube with a compression member disposed over the catheter. 
     In accordance with a sixth aspect, a method for delivering a composition, such as a composition comprising a therapeutic agent, to an intrathecal space of a patient is described that includes locating a port secured in a subcutaneous position within a patient through tissue of the patient, inserting a distal tip of a needle through the tissue of the patient, through a septum of the port, and into a chamber of the port, dispensing the composition into the chamber, and distributing the composition into the intrathecal space of the patient through a catheter fluidly coupled to the port. 
     According to some forms, locating the port can include one or more of the following: imaging radiopaque portions of the port; palpating raised protrusions of the port; palpating suture plugs coupled to the port; mating a guide tool with a raised lip of the port; actuating an actuator having a movable portion providing at least one of tactile or visual feedback; emitting an electric field to vibrate piezoelectric crystals mounted to the port; attracting a metallic guide to one or more magnets distributed about the septum within the port; attracting a magnetic guide to one or more metallic portions distributed about the septum of the port; imaging metallic and non-metallic components of the port; illuminating one or more LEDs mounted to the port; communicating with one or more sensors disposed within the port with an external device to provide one or more of: distance, alignment, orientation, targeting, or location data relative to the external device; or detecting an aqueous gel material within the port by ultrasound. 
     According to some forms, dispensing the composition into the chamber can include dispensing one or more therapeutic agents described further below. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The above needs are at least partially met through provision of the embodiments described in the following detailed description, particularly when studied in conjunction with the drawings, wherein: 
         FIG. 1  is a perspective view of a first example port for a fluid delivery system in accordance with various embodiments; 
         FIG. 2  is a cross-sectional view of the port of  FIG. 1  showing an interior chamber and catheter connection assembly in accordance with various embodiments; 
         FIG. 3  is a perspective view of a second example port for a fluid delivery system in accordance with various embodiments; 
         FIG. 4  is a cross-section view of the port of  FIG. 3  showing an interior chamber and catheter connection assembly in accordance with various embodiments; 
         FIG. 5  is a bottom perspective view of the port of  FIG. 3  in accordance with various embodiments; 
         FIG. 6  is a cross-sectional vie of the port of  FIG. 3  showing fastener connections between a body and cap of the port in accordance with various embodiments; 
         FIG. 7  is a schematic view of a fluid delivery system in accordance with various embodiments; 
         FIG. 8  is a top plan view of a port for a fluid delivery system having a first example body configuration for location feedback in accordance with various embodiments; 
         FIG. 9  is a top plan view of a port for a fluid delivery system having a second example body configuration for location feedback in accordance with various embodiments; 
         FIG. 10  is a top plan view of a port for a fluid delivery system having a third example body configuration for location feedback in accordance with various embodiments; 
         FIG. 11  is a top plan view of a port for a fluid delivery system having a fourth example body configuration for location feedback in accordance with various embodiments; 
         FIG. 12  is a perspective view of a first example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 13  is a perspective view of a second example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 14  is a perspective view of a third example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 15  is a perspective view of a fourth example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 16  is a top plan view of a fifth example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 17  is a side view of the port of  FIG. 16  showing first and second states of a lever of the port in accordance with various embodiments; 
         FIG. 18  is a top plan view of a sixth example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 19  is a top plan view of a seventh example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 20  is a top plan view of a eighth example port for a fluid delivery system having location feedback features with an external device in accordance with various embodiments; 
         FIG. 21  is a side elevational view of the port of  FIG. 20  in accordance with various embodiments; 
         FIG. 22  is a top plan view of a ninth example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 23  is a perspective view of a tenth example port for a fluid delivery system having location feedback features with an external guide in accordance with various embodiments; 
         FIG. 24  is a top plan view of an eleventh example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 25  is a side elevational view of the port of  FIG. 24  with an external metallic guide in accordance with various embodiments; 
         FIG. 26  is a perspective view of a twelfth example port for a fluid delivery system having location feedback features with an external magnetic guide in accordance with various embodiments; 
         FIG. 27  is a side elevational view of a thirteenth example port for a fluid delivery system having location feedback features with an external metal detector in accordance with various embodiments; 
         FIG. 28  is a perspective view of a fourteenth example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 29  is a perspective view of a fifteenth example port for a fluid delivery system having location feedback features with an external device in accordance with various embodiments; 
         FIG. 30  is a top plan view of a sixteenth example port for a fluid delivery system having location feedback features in accordance with various embodiments; 
         FIG. 31  is a side plan view of the port of  FIG. 30  in accordance with various embodiments; 
         FIG. 32  is a perspective view of the port of  FIG. 30  with an external device in accordance with various embodiments; 
         FIG. 33  is a top plan view of a fluid delivery system including a port and catheter in accordance with various embodiments; 
         FIG. 34 a    is a cross-sectional view of a catheter having a first example construction in accordance with various embodiments; 
         FIG. 34 b    is a cross-sectional view of a catheter having a second example construction in accordance with various embodiments; 
         FIG. 35 a    is a schematic view of a fluid delivery system for implantation in the intrathecal space of a patient and portion of a catheter of the fluid delivery system in accordance with various embodiments; 
         FIG. 35 b    is a schematic view of a catheter inserted into a dura of a patient with a grommet extending around the catheter and engaging the dura in accordance with various embodiments; 
         FIG. 35 c    is a cross-sectional view of a plug for a catheter inserted into the fascia in accordance with various embodiments; 
         FIG. 35 d    is a perspective view of the plug of  FIG. 35 c    in accordance with various embodiments; 
         FIG. 36  is a sectional view of a distal end of the catheter of  FIG. 34  in accordance with various embodiments; 
         FIG. 37 a    is a cross-sectional view of a first example distal end for a catheter in accordance with various embodiments; 
         FIG. 37 b    is a cross-sectional view of a second example distal end for a catheter in accordance with various embodiments; 
         FIG. 37 c    is a cross-sectional view of a third example distal end for a catheter in accordance with various embodiments; 
         FIG. 37 d    is a cross-sectional view of a fourth example distal end for a catheter in accordance with various embodiments; 
         FIG. 38 a    is a sectional view of an intermediate portion of the catheter of  FIG. 34  showing first example radial outlets in accordance with various embodiments; 
         FIG. 38 b    is a sectional view of a portion of a catheter showing second example radial outlets in accordance with various embodiments; 
         FIG. 38 c    is a sectional view of a portion of a catheter showing third example radial outlets in accordance with various embodiments; 
         FIG. 38 d    is a sectional view of a portion of a catheter showing fourth example radial outlets in accordance with various embodiments; 
         FIG. 39  is a cross-sectional view of a first example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 40  is a cross-sectional view of a second example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 41  is a cross-sectional view of a third example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 42  is a cross-sectional view of a fourth example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 43  is a cross-sectional view of a fifth example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 44  is a cross-sectional view of a sixth example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 45  is a cross-sectional view of a seventh example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 46  is a cross-sectional view of an eighth example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 47  is a cross-sectional view of a ninth example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 48  is a cross-sectional view of a tenth catheter and port connection assembly in accordance with various embodiments; 
         FIG. 49  is a cross-sectional view of an eleventh example catheter and port connection assembly in accordance with various embodiments; 
         FIG. 50  is a cross-sectional view of an example port for a fluid delivery system having a side septum for a stylet in accordance with various embodiments; and 
         FIG. 51  is a cross-sectional view of an example port for a fluid delivery system being impregnated or pre-loaded with one or more dosages of a medication in accordance with various embodiments. 
     
    
    
     DETAILED DESCRIPTION 
     The fluid delivery devices, systems and methods described herein include a sterile, implantable intrathecal catheter and subcutaneous port. The fluid delivery devices are designed to facilitate intrathecal access in patients with normal spines, as well as patients with spinal deformities and/or instrumentation for whom intrathecal access, and the associated fluid administration and sampling, via lumbar puncture (LP) is complicated or not possible. By utilizing the devices, systems, and methods provided, the need for repeat anesthesia and surgery each time intrathecal access is needed in these patients can be avoided. 
     The fluid delivery systems can be used to administer fluids (optionally including one or more therapeutic agents) to patients by means of manual bolus injection, standard syringe pump or Pulsar auto-injector pump. Therapeutics approved for bolus intrathecal administration would be infused into the patient through the subcutaneous port by palpating the port to identify the septum, and accessing the septum with a needle, such as a standard non-coring Huber needle. Additionally, or alternatively, the system can include a non-invasive detection guide. In some versions, the systems can utilize magnetic components, sensors, light sources, and/or transmitters to provide location aid to a clinician. 
     An example port  100  suitable for subcutaneous implantation is shown in  FIGS. 1 and 2 . The port  100  includes a body  102 , a cap  104  coupled to the body  102 , and a septum  106  providing needle access to a chamber  108  defined in the body  102 . The chamber  108  includes a delivery opening  110  to dispense fluids to desired areas, described in more detail below. The port  100  can be anchored on a desired location within a patient selected by a clinician, such as a bony structure. For example, the body  102  can include one or more openings  112  extending therethrough to receive fasteners to mount the port  100  to the bony structure. Further, the openings  112  can be recessed with respect to adjacent portions of the body  102 , so that head portions of the fasteners do not protrude beyond the body surface or only a portion thereof protrudes beyond the body surface. As shown, the port  100  can have a tapered profile with smooth exterior surfaces. This configuration advantageously mitigates skin erosion when the port  100  is implanted in a desired subcutaneous location. 
     As shown in  FIG. 2 , the body  102  has a frusto-conical shape with an outwardly tapering exterior surface  114  extending from an upper shoulder surface  116  to a bottom wall portion  118 . The body  102  defines an interior cavity  120  having an opening  122  opposite the bottom wall portion  118 . In the illustrated form, the body  102  extends around the interior cavity  120  in an annular configuration. The interior cavity  120  includes a lower portion defining the chamber  108  and an upper septum receiving portion  124 . The chamber  108  can have smaller cross-sectional dimensions than the upper portion  124 , such that a shoulder  126  extends between the upper portion  124  and the chamber  108  of the interior cavity  120 . In the illustrated form, the upper portion  124  and the chamber  108  are cylindrical with the chamber  108  having a smaller diameter than the upper portion  124 . 
     The upper portion  124  is sized to receive the septum  106  therein. For example, the septum  106  can have a disk shaped configuration and the diameter of the upper portion  124  can be approximately equal to, e.g., within 2 mm, to the diameter of the septum  106  so that the septum  106  is securely received within the upper portion  124 . Further, as shown in  FIG. 2 , the shoulder  126  can include an upwardly projecting lip  128  that extends around an interior edge thereof and is configured to engage the septum  106 . 
     In order to secure the septum  106  within the port  100 , the cap  104  is coupled to the body  102  to trap the septum  106  therebetween. The cap  104  defines an interior opening  130  extending therethrough to provide needle access to the septum  106 . In the illustrated form, the cap  104  is annular with a generally triangular cross-section in a longitudinal direction. So configured, the cap  104  includes an interior surface  132  that extends around and tapers downwardly toward the opening  130 , an exterior surface  134  that tapers downwardly to the body  102 , and a top edge  135 . As shown, the cap  104  extends over an upper surface of the septum  106 , with the cap  104  deforming the septum  106  and causing the upper surface of the septum  106  to protrude through the opening  130 . With this configuration, the interior surface  132  can advantageously redirect a needle that has missed the septum  106  to the opening  130  and to the upper surface of the septum  106 . 
     As shown, the cap  104  can further include a downwardly extending sidewall  136  that defines a portion of the exterior surface  134  and that projects along the body  102 . In the illustrated form, the body  102  includes an outwardly opening groove  138  in the exterior surface  114  and the sidewall  136  of the cap  104  includes an inwardly projecting lip  140 . So configured, the cap  104  can be press fit onto the body  102 , deflecting the sidewall  136  until the lip  140  snap fits into the groove  138 . With the cap  104  secured to the body  102 , the cap  104  has an annular portion  142  extending over the cavity opening  122  and, in some versions, includes a downwardly projecting lip  144  extending therearound. So configured, an outer portion  146  of the septum  106  is trapped between the annular portion  142  of the cap  104  and the shoulder  126  of the body  102 , while a central portion  148  of the septum  106  provides a clear path to the chamber  108 . The lips  128 ,  144  project towards one another on opposite sides of the septum  106  to pinch the septum  106  therebetween to both secure the septum  106  and ensure a fluid tight seal. In some versions, the thickness and diameter of the septum  106  can be optimized to provide a low-profile port  100 , while also providing a sufficiently large diameter for the central portion  148  so that the septum  106  can be easily located and identified through tissue. Alternatively, the cap  104  can also include an internal thread configured to engage an external thread of the body  102  to secure the cap  104  thereto. In another example, the cap  104  can be ultrasonically welded to the body  102 . 
     Another example port  200  suitable for subcutaneous implantation is shown in  FIGS. 3-6 . The port  200  of this form includes many similar features to the above described port  100  and, as such, only the differences will be described herein with components having similar reference characters. For example, the port  200  of this form includes a body  202 , a cap  204  coupled to the body  202 , and a septum  206  providing needle access to a chamber  208  defined in the body  202 . The chamber  208  includes a delivery opening  210  to dispense fluids to desired areas, described in more detail below. The port  200  can be anchored on a desired location within a patient selected by a clinician, such as a bony structure. 
     In this form, the cap  204  and body  202  couple together so that exterior surfaces  234 ,  214  thereof align giving the port  200  a substantially unbroken exterior with a frusto-conical shape. Further, as shown in  FIG. 2 , the body  202  includes an intermediate upstanding wall portion  250  disposed between a shoulder  226  of a body cavity  220  and an exterior shoulder  252 . The cap  204  seats on the exterior shoulder  252  of the body  202  with an inwardly extending top portion  254  seating on an upper surface  216  of the wall  250  with an annular portion  242  engaging the septum  206  as described above. 
     Another suitable method for securing the cap  204  to the body  202  is shown in  FIGS. 5 and 6 . In this form, the body  202  includes a plurality of throughbores  256  extending therethrough and the cap  204  includes corresponding bores  258  that align with the throughbores  256  of the body  202 . So configured, fasteners  260  can be inserted through the bottom wall  218  of the body  202  and secured to the cap  204 , such as by threading as shown. As the fasteners  260  tighten, the annular portion  242  of the cap  104  and the shoulder  126  of the body  202  traps the outer portion  246  of the septum  106  therebetween, while providing a clear path to the chamber  208  through the central portion  248  of the septum  206 . If desired, the body  202  can include counterbores  262  in the bottom wall  218  thereof so that heads  264  of the fasteners  260  do not protrude beyond the bottom wall  218 . 
     The components of the port  100 ,  200  can be formed from any suitable material. In some versions, one or more of the body  102 ,  202 , cap  104 ,  204 , septum  106 ,  206 , or portions thereof, can be radiopaque for easy visualization under a fluoroscope or in an x-ray. In some examples, inner structures of the port  100 ,  200  can be polyether ether ketone (PEEK) or can have a PEEK layer on a metal housing, such as Titanium. Further, an outer shell, or needle facing surfaces can be metal, such as Titanium. 
     As discussed above, the port  100 ,  200  can include one or more features to aid in locating the port  100 ,  200  in a subcutaneous position. As shown in  FIG. 7 , a clinician can palpate and visually inspect the tissue of patient in order to locate the port  100 ,  200 . In some forms, the body  102 ,  202  can include a housing  300  having a distinctive shape providing palpatory feedback to a clinician through the tissue of patient. For example, the housing  300  can have an oval or track-shaped cross-section as shown in  FIG. 8 , can have three or more outwardly extending branches  302  as shown in  FIG. 9 , can have a triangular cross-section as shown in  FIG. 10 , or can have an oval or track-shaped cross-section with a prong  304  extending outwardly from a side edge  306  thereof as shown in  FIG. 11 . 
     In another example, the port  100 ,  200  can include protruding features  310  providing distinct palpatory feedback to a clinician through the tissue of a patient by virtue of differences in surface height as compared to adjacent portions of the cap  104 ,  204  and/or body  102 ,  202 . In some examples, the cap  104 ,  204  can include a plurality of raised protrusions  312  extending above the top edge  135 ,  235  thereof and distributed around the opening  130 ,  230  as shown in  FIGS. 12-14 . The raised protrusions  312  can be disposed on the top edge  135 ,  235 , the interior surface  132 ,  232 , the exterior surface  134 ,  234 , or combinations thereof. The raised protrusions  312  can take any suitable form, including rounded nodes as shown in  FIG. 12 , arcs as shown in  FIG. 13 , and a raised wall or lip as shown in  FIG. 14 . The features  310  can have a rounded or rectangular profile and can be provided in any suitable amount, such as four as shown in the figures, two, three, five, six, or more. Of course, while the protruding features  310  have been described with reference to the cap  104 ,  204 , the body  102 ,  202  can also or alternatively include similarly configured protruding features  310 . 
     In another example, the port  100 ,  200  can include upwardly protruding suture plugs  314 , which can be filled with silicone, to provide palpatory feedback to a clinician through the tissue of patient. As shown in  FIG. 15 , a base  316  of the suture plugs  314  can be mounted to the body  102 ,  202  and distributed around the central septum  106 ,  206  with a shaft  318  extending upwardly from the base  316  having a distal end  320  disposed above the top edge  135 ,  235  of the cap  104 ,  204 . The suture plugs  314  can have any suitable cross-section, such as circular or rectangular, and can be provided in any suitable amount, such as four as shown in the figures, two, three, five, six, or more. Of course, while the suture plugs  314  have been described with reference to the body  102 ,  202 , the cap  104 ,  204  can also or alternatively include similarly configured suture plugs  314 . 
     In another example, as shown in  FIGS. 16 and 17 , the port  100 ,  200  can include a lever  322  pivotable about a pin  324 . The lever  322  is disposed within a recess  326  within the cap  104 ,  204  or body  102 ,  202  and has an angled configuration, so that a portion  328  is always projecting out of the recess  326 . With this configuration, a clinician can manipulate the lever  322  and the pivoting action of the lever  322  will provide tactile and visual feedback through the tissue. By another approach, the port  100 ,  200  can include a switch  330 , such as a pushbutton or slide switch. Actuation of the switch  330  can provide tactile feedback to a clinician. Further, the switch  330  can be electrically coupled to an LED or other light source  332 , such that actuation of the switch  330  energizes the LED  332  providing visual feedback to a clinician upon actuation. The lever  322 , recess  326 , switch  330 , and/or LED  332  can be encapsulated or covered with a protective layer  334  adhered or otherwise secured to the port  100 ,  200  to prevent tissue from interfering with the feedback response and movement of the components. 
     In another example, as shown in  FIGS. 18 and 19 , the port  100 ,  200  can include a plurality of LEDs or other light sources  336  embedded into the body  102 ,  202  and/or cap  104 ,  204 . The LEDs  336  can be electrically coupled together and to a first coil  338 . So configured, a clinician can bring an external device  340  having a second coil  342  emitting an electromagnetic field into range of the first coil  338  to transfer energy and thereby energize the LEDs  336  providing visual feedback to the clinician. In a first form as shown in  FIG. 18 , the LEDs  336  can be disposed around the opening  130 ,  230  and directed inwardly to selectively illuminate the septum  106 ,  206 . In a second form as shown in  FIG. 19 , the LEDs  336  can be disposed around the opening  130  and directed upwardly to selectively provide illumination through the tissue of the patient. Any number of LEDs  336  can be utilized, such as four or five as shown, two, three, six, or more. 
     In another example, as shown in  FIG. 20 , the port  100 ,  200  can include a plurality of piezoelectric crystals  344  embedded into the body  102 ,  202  and/or cap  104 ,  204 . So configured, a clinician can bring an external device  346  emitting an electric field into range of the piezoelectric crystals  344  to cause the piezoelectric crystals  344  to vibrate and provide tactical and visual feedback to the clinician. If desired, as shown in  FIG. 21 , the piezoelectric crystals  344  can be distributed around the opening  130 ,  230  and sized to protrude from adjacent surfaces of the body  102 ,  202  and/or cap  104 ,  204  to provide tactile feedback similar to the above-described protruding features  310 . For example, the piezoelectric crystals  344  can extend past the top edge  135 ,  235  of the cap  104 ,  204 . 
     Further, palpating the piezoelectric crystals  344  causes the piezoelectric crystals  344  to emit a voltage. Accordingly, as shown in  FIG. 22 , the port  100 ,  200  can include a plurality of LEDs or other light sources  348  embedded into the body  102 ,  202  and/or cap  104 ,  204 . The LEDs  348  can be electrically coupled together and to the piezoelectric crystals  344 . So configured, a clinician can find the piezoelectric crystals  344  through vibration and subsequently palpate the piezoelectric crystals  344  to emit a voltage and energize the LEDs  348 . The LEDs  348  can be configured to illuminate the septum  106 ,  206  and/or outwardly as described above with respect to  FIGS. 18 and 19 . 
     In another example, as shown in  FIG. 23 , the top edge  135 ,  235  of the cap  104 ,  204  can have a raised lip  350  and an external guide  352  can include a central opening  354  configured to mate with and around the raised lip  350 . The external guide  352  can further include a skirt  356  depending downwardly from the central opening  354  so that a profile of the skirt  356  is complementary to external surfaces  114 ,  214 ,  134 ,  234  of the body  102 ,  202  and cap  104 ,  204 . So configured, a clinician can locate the port  100 ,  200  and place the guide  352  onto the port  100 ,  200  through the tissue of the patient and the opening  354  and skirt  356  will orient the guide  352  to non-invasively identify the location of the septum  106 ,  206  through the opening  354 . 
     In another example, as shown in  FIGS. 24 and 25 , the port  100 ,  200  can include a plurality of magnets  358  embedded into the body  102 ,  202  and/or cap  104 ,  204  and distributed around the opening  130 ,  230 . So configured, a clinician can bring an external metallic ring  360  into range of the magnets  358  and the magnets  358  will attract the ring  360  to the port  100 ,  200  through the tissue of the patient. The magnets  358  orient the ring  360  to frame the opening  130 ,  230  on top of the tissue of the patient to provide an external indication of the location of the septum  106 ,  206 . Any number of magnets  358  can be utilized, such as three as shown, two, four, five, six, or more, to optimize the strength and locationing of the guide  352 . 
     In an alternative example, as shown in  FIG. 26 , the port  100 ,  200  can include a metallic ring  362  extending around the opening  130 ,  230  and mounted to or forming a portion of the body  102 ,  202 , and/or cap  104 ,  204 . Although an unbroken ring  362  is shown, it will be understood that the ring  362  can be formed from a plurality of spaced portions. With this configuration, a clinician can bring an external magnetic guide  364  having an interior opening  366  into range of the metallic ring  362  and the magnetic guide  364  will be attracted to the metallic ring  362  of the port  100 ,  200  through the tissue of the patient. The magnetic guide  364  is then oriented and held on the tissue of the patient so that the opening  366  frames the opening  130 ,  230  to provide an external indication of the location of the septum  106 ,  206 . The magnetic guide  364  can be formed entirely of a magnetic material or can include a plurality of magnets mounted thereto. Any number of magnets can be utilized to optimize the strength and locationing of the guide  364 . 
     In another example, as shown in  FIG. 27 , the port  100 ,  200  can include metallic portions or components  368  of a sufficient size to be detectable by an external metal detector  370 . So configured, a clinician can operate the metal detector  370  and move the detector  370  along the patient&#39;s body until the detector  370  indicates the presence of the metallic components  368 . Thereafter, the clinician can palpate the tissue to identify the location of the septum  106 ,  206 . The metallic components  368  can be fasteners, layers, or portions of the body  102 ,  202  and/or cap  104 ,  204 . In an alternative example, the port  100 ,  200  can include a transmitter  372  can be passive and energized by an external device  370  with a receiver  374 , such as that described above with respect to  FIGS. 18 and 19 . So configured, the can operate the device  370  and move the device  370  along the patient&#39;s body until the device  370  energizes the transmitter  372  and receives a signal from the transmitter  372 . Thereafter, the clinician can palpate the tissue to identify the location of the septum  106 ,  206 . 
     In an alternative example, as shown in  FIG. 28 , the port  100 ,  200  can include a combination of metallic and non-metallic components to provide distinct appearance under imaging. For example, the port  100 ,  200  can include rings of metallic and non-metallic portions, the body  102 ,  202  can be metallic, the cap  104 ,  204  can be metallic, or combinations thereof. In further examples, the septum  106 ,  206  can be radiopaque so that a clinician can clearly distinguish between the various components and the location of the septum  106 ,  206  under imaging. Alternatively, the septum  106 ,  206  can be filled with aqueous gel materials that are detectable by an ultrasound machine. 
     In another example, as shown in  FIG. 29 , the port  100 ,  200  can be configured so that the septum  106 ,  206  can be raised through the central opening  130 ,  230 . The septum  106 ,  206  can be raised by a lifting mechanism  376  disposed within the port  100 ,  200  and engaging the septum  106 ,  206 . The lifting mechanism  376  can be any suitable device, including actuators, springs, motors, magnets, and so forth. The lifting mechanism  376  can be operable in response to communication or influence by an external tool  378 . For example, the tool  378  can send a wireless command to the lifting mechanism  376  and/or can include metallic or magnetic components. The septum  106 ,  206  can be lifted to a raised position as shown to provide visible and tactile feedback to a clinician for locating the port  100 ,  200 . Further, the raised septum  106 ,  206  can be utilized during infusion, described in more detail below. 
     In another example, as shown in  FIGS. 30-32 , the port  100 ,  200  can include one or more sensors  380  embedded within the body  102 ,  202  and/or cap  104 ,  204  thereof. The sensors  380  can be passive and energized by an external device  382 , such as that described above with respect to  FIGS. 18 and 19 . The external device  382  can include a housing  384  with corresponding sensors  386  and a processor  388 . The sensors  380 ,  386  can be one or more of: proximity, infrared, pressure, ultrasonic, light, temperature, or tilt sensors. When energized, the sensors  380 ,  386  can provide data to the processor  388  of the external device  382  regarding the distance, axis alignment, orientation, relative angles, or combinations of the sensors  386  of the external device  382  relative to the sensors  380  of the port  100 ,  200 . For example, the sensors  380 ,  386  can identify vertical alignment or misalignment therebetween, shown by vertical alignment X 1  and angled alignment X 2  in  FIG. 32 . Further, readings from the sensors  380 ,  386  can identify horizontal alignment, shown by the angle X 3  in  FIG. 32 . The processor  388  can then analyze the data to calculate a position and/or orientation of the external device  382  relative to the port  100 ,  200  and provide feedback to a clinician. The external device  382  can provide feedback by any suitable mechanism, such as through lights  390 , sounds through a speaker  392 , a vibration device  394 , or any other visual or tactile feedback to indicate that the external device  382  is properly aligned with the port  100 ,  200  for optimized needle insertion into and through the septum  106 ,  206 . In further examples, the external device  382  can utilize multicolored lights  390  or other distinguishable feedback to communicate degrees of accuracy with different designated colors for alignment, such as red for misalignment, yellow for near alignment, and green for correct alignment. 
     Turning now to  FIGS. 33-35 , a catheter  400  can be coupled to the port  100 ,  200  to be fluidly coupled to the delivery opening  110  of the chamber  108  to dispense fluids to desired areas. The catheter  400  can be utilized to provide homogeneous delivery of composition (optionally comprising one or more therapeutic agents) to the intrathecal space of a patient. As such, the catheter  400  can be configured to extend along the substantially the entire length of a patient&#39;s spinal column or along any portion thereof. As shown, the catheter  400  includes an elongate, tubular body  402  having a central passage  404  extending from a proximal end  406  configured to couple to the port  100 ,  200  to a distal end  408 . 
     The catheter  400  can be configured for long term implantation into a patient and, as such, can be constructed from materials to make the catheter soft, flexible, and kink resistant. Further, in some versions, the catheter  400  can be configured to complex spine patients, e.g., scoliosis, the materials can provide column strength, break resistance, and stiffness so that the catheter  400  can be threadable during insertion. Pursuant to this, some or all of the catheter  400  can have a three layer construction as shown in  FIGS. 34 a  and 34 b   , including an inner lumen  410 , a reinforcement layer  412 , and an outer jacket  414 . For example, the inner lumen  410  can be polytetrafluoroethylene (PTFE) or polyurethane (PU) and the outer jacket  414  can be an extrusion of PTSE, PU, or silicone and can include a hydrophilic coating. In some versions, the reinforcement layer  412  can be provided in the proximal end  406  to increase a hoop strength of the catheter  400  allowing a relatively higher compression without crushing damage, which may compromise the interior diameter of the catheter  400 . This can advantageously be utilized to provide a strong connection and seal with the port  100 ,  200 , several examples of which are described below. In a first example, as shown in  FIG. 34 a   , the reinforcement layer  412  can be a suitable braided metal, such as stainless steel, or polymer, such as polyimide, polyethylene terephthalate (PET), and so forth. In a second example, as shown in  FIG. 34 b   , the reinforcement layer  412  can be a series of rings or a coil causing the catheter to have outwardly extending radial protrusions  413 . The radial protrusions  413  can be utilized in the connection with the port  100 ,  200 , described in more detail below, subsidize the tensile strength of the connection. 
     As shown in  FIG. 36 , the distal end  408  of the catheter  400  can include an atraumatic tip  416  having a rounded profile and a distal outlet  418  extending therethrough to the central passage  404 . The distal outlet  418  can be disposed along a longitudinal axis of the catheter  400  or can be disposed at an angle with respect thereto. The rounded profile of the atraumatic tip  416  allows the distal end  408  to be easily deflectable during insertion to avoid the end  408  from becoming lodged and aid in the catheter  400  being threaded through the intrathecal space. Further, the atraumatic tip  416  can allow implantation into the intrathecal space without damaging or exiting the intrathecal space. 
     One example atraumatic tip  416  is shown in  FIG. 37 a   . The tip  416  of this form includes a narrowing choke  420  connecting the central passage  404  to the distal outlet  418  where the choke  420  has a smaller diameter than the central passage  404  and distal outlet  418  creating a venturi effect, lowering fluid pressure and increasing fluid velocity through the tip  416 . If desired, the distal outlet  418  can include a mixing chamber  428  having an inner diameter that is equal to or larger than the inner diameter of the central passage  404 . Further, the distal outlet  418  can include a reduced-diameter opening  430  relative to the inner diameter of the mixing chamber  428 . The opening  430  gives the distal outlet  418  a nozzle effect. Further, the tip  416  includes one or more side passages  422 , such as two, three, four, or more, that extend from radial openings  424  to fluidly connect to the distal outlet  418 . As shown, the side passages  422  can extend at an angle with respect to the longitudinal axis of the catheter  400  so that interior openings  426  of the side passages  422  are closer to the distal end  408  of the catheter  400  than the radial openings  424 . With this configuration, the choke  420  creates a higher flow of therapeutic fluid through the catheter  400  with a lower pressure. Due to this, cerebrospinal fluid is drawn into the catheter  400  through the side passages  422  to join the flow of fluid creating a higher mass flow. Moreover, in the event that the distal outlet  418  becomes blocked or occluded, the side passages  422  can serve as secondary outlets for the catheter distal end  408 . 
     Another example atraumatic tip  416  is shown in  FIG. 37 b   . In this form, the distal outlet  418  includes a mixing chamber  432  having an inner diameter larger than the inner diameter of the central passage  404  and a radially-tapering transition portion  434  extending between the central passage  404  and the mixing chamber  432 . As shown, the distal outlet  418  can have a constant inner diameter extending from the mixing chamber to an outlet opening  436 . The tip  416  can further include one or more side passages  438 , such as two, three, four, or more, configured similar to the side passages  422  of the above form extending at an angle with respect to the longitudinal axis of the catheter. As shown, the side passages  438  can connect to the transition portion  434  to introduce cerebrospinal fluid to the flow of fluid through the catheter  400  providing flow mass amplification within the mixing chamber  432 . 
     Another example atraumatic tip  416  is shown in  FIG. 37 c    that includes side passages  440  and a narrowing choke  442 . In this form, the side passages  440  extend radially through the catheter  400  and connect to the central passage  404  in the choke  442 . Further, the inner diameter of the central passage  404  and an outlet opening  444  can be generally equal. 
     Another example atraumatic tip  416  is shown in  FIG. 37 d   . In this form, the distal outlet  418  can include a reduced-diameter opening  446  relative to the inner diameter of the central passage  404 . The opening  446  gives the distal outlet  418  a nozzle effect. 
     For some applications, it may be desirable to dispense a composition along a length of the catheter  400  into the intrathecal space of a patient. To achieve this, as shown in  FIGS. 38 a -38 d   , the catheter  400  can include one or more radial outlets  448  disposed along a length of the catheter  400  between the proximal and distal ends  406 ,  408  thereof. In a first example form, as shown in  FIG. 38 a   , the radial outlets  448  can be disposed in a spiral configuration extending along a length and around a circumference of the catheter  400 . The spiral configuration of this form ensures that the composition has a maximized exposure and spread within the intrathecal space. 
     In a second example form, as shown in  FIG. 38 b   , the radial outlets  448  can be disposed in one or more rings  450  with the radial outlets  448  distributed about a circumference of the catheter  400 . The rings  450  can be spaced from one another along the axial length of the catheter  400  and can be disposed within a plane generally normal to the axial length of the catheter  400 . In a third example form, as shown in  FIG. 38 c   , the radial outlets  448  can be disposed in one or more bands  452  running the axial length of the catheter  400 . The catheter  400  can include one band  452  to distribute fluid in one radial direction, two, three, four, or more, as desired. In another example, as shown in  FIG. 38 d   , the radial outlets  448  can include both one or more rings  450  and one or more bands  452 . 
     In some versions, the distal and radial outlets  418 ,  448  can be sized to achieve a desired fluid distribution. In a first example, the distal and radial outlets  418 ,  448  can be sized so that a majority of fluid is dispensed through the distal outlet  418 . In a second example, the distal and radial outlets  418 ,  448  can be sized so that an amount of fluid dispensed through the distal outlet  418  is generally equal to an amount of fluid dispensed through the radial outlets  448 . 
     In order to confirm that the catheter  400  has been correctly implanted into the intrathecal space and/or is in a fully functioning form, the catheter  400  may include one or more radiopaque markings or components to be visible under imaging. For example, the entire catheter  400  can be radiopaque or, as shown in  FIG. 35 a   , the catheter  400  can include radiopaque markings  454  disposed at featured locations, such as below the distal end  406 , adjacent to a start of the radial outlets  448 , adjacent to an end of the radial outlets  448 , and so forth. 
     In some examples, the catheter  400  can be provided with an extended length so that a clinician can cut the catheter  400  to a desired length for a particular patient. For example, the catheter  400  can be provided to the clinician with a length up to 140 cm. Further, the catheter  400  described herein can be a 3-fr, 1 mm outer diameter catheter. Other suitable outer diameters for the catheter  400  can be in the range of about 0.25 mm to about 1.5 mm, or in the range of about 0.5 mm to about 1.25 mm, or in the range of about 0.75 mm to about 1.0 mm. 
     The spinal column of a patient is surrounded by a dura  458  that can be penetrated by a suitable instrument, such as a Tuohy needle, to create an opening  456  for the insertion of a catheter  400 , configured as described above. As shown in  FIG. 35 b   , in order to minimize or prevent tearing of the opening  456  and leakage of cerebrospinal fluid, a clinician can utilize a grommet  460  to abut the dura  458  and extend around the opening  456  therein. The grommet  460  can include a sleeve portion  462  sized to extend around the catheter  400  and a flange portion  464  projecting outwardly from the sleeve portion  462  and configured to be placed on the dura  458  over and around the opening  456 . 
     In some versions, the catheter  400  can further be provided or implanted along with a plug  466  having a body  468  with a passage  470  extending therethrough for reception of the catheter  400 . The passage  470  extends through the plug body  468  from a distal end  472  to an opposite, proximal end  474  thereof. As shown, one or both of the ends  472 ,  474  can have a beveled, frusto-conical configuration. Further, the body  468  can have a bent configuration with the distal end  472  at an angle with respect to the proximal end  474 . For example, the body  468  can include a bend  476 , that can be generally 90 degrees, e.g., within 5 to 10 degrees, as shown, although other acute or obtuse angles can also be utilized. In order to thread the catheter  400  through the plug  466 , the body  468  can include an opening  478  that extends through the body  468  from the passage  470  to an exterior  480  of the plug  466 . A clinician can utilize the opening  478  to manipulate the catheter  400  through the plug body  468  and out through the distal end  472 . 
     A fascia  482  extends around the dura  458  and, as such, the fascia  482  can also be penetrated by the instrument to create an opening  484  therein in addition to the opening  456  in the dura  458 . The plug  466  can advantageously be implanted through the opening  484  in the fascia  482  to create a seal with the tissue of the fascia  482  to minimize or prevent leakage of cerebrospinal fluid. The beveled configuration of the distal end  472  can also aid a clinician in inserting the plug  466  through the fascia  482 . 
     In one approach, shown in broken lines in  FIG. 35 c   , the plug  466  can be inserted into the fascia  482  until the distal end  472  abuts the dura  458 . So configured, the distal end  472  can extend around the opening  456  to minimize or prevent tearing and cerebrospinal fluid leakage. In another approach, shown in solid lines in  FIG. 35 c   , the plug  466  can be inserted into the fascia  482  with the distal end  472  spaced from the dura  458 . In either approach, after the plug  466  is positioned, a clinician can stitch up the opening  484  in the fascia  482  with a suture  486  so that some tissue  488  of the suture  486  is captured between the suture  486  and the plug body  468 . Thereafter, when the clinician tightens the suture  486 , the tissue  488  is tightly captured between the suture  486  and the plug body  468  creating a seal preventing or minimizing the leakage of cerebrospinal fluid through the fascia opening  484 . In some versions, the plug body  468  can include an annular recess  490  extending therearound, or a plurality of recesses distributed around the circumference, adjacent to the distal end  472 . When the suture  486  is tightened, the tissue  488  can be drawn into the recess  488  preventing or minimizing subsequent movement of the suture  486 . 
     As shown, the body  468  can further include outwardly projecting tabs  492  having openings  494  extending therethough. A clinician can utilize the tabs  492  to secure the proximal end  474  of the plug body  468  to the fascia  482  with sutures  492 . Advantageously, the bent configuration of the body  468  allows the plug proximal end  474  to extend along the fascia  482  for a compact configuration after implantation. In one form, the plug  466  can be made of silicone or other suitable material. 
     In an alternative or additional approach, the catheter  400  can include a portion with an outwardly tapered configuration where the increased outer diameter is configured to engage the opening  456  in the dura  458  to minimize or prevent tearing. 
     As briefly described above, the catheter  400  can be configured to couple to the port  100 ,  200  to be fluidly coupled to the delivery opening  110 ,  210  of the chamber  108 ,  208 . This can be achieved in a number of suitable connection assemblies  500 , some or all of which can advantageously be free of metal components. In a first example, shown in  FIGS. 2 and 4 , the port  100 ,  200  can include a cylindrical cavity  502  extending radially through the body  102 ,  202  with the delivery opening  110 ,  210  at an interior end  504  and an open exterior end  506 . The cylindrical cavity  502  can include a threaded portion  508  and a counterbore  510  at the open exterior end  506 . Next, an annular gasket  512  can be placed over the proximal end  406  of the catheter  400  and the assembled gasket  512  and catheter  400  is inserted into the cavity  502  until the gasket  512  and catheter  400  abut the interior end  504  thereof. As shown, this aligns the central passage  404  of the catheter  400  with the delivery opening  110 ,  210 . To secure the catheter  400  to the port  100 ,  200  and create a fluid tight seal, a ferrule  514  extending around the catheter  400  can be inserted into the cavity  502  to engage the threaded portion  508 . As the ferrule  514  is threaded into the cavity  502 , the ferrule  514  engages the gasket  512  and causes the gasket  512  to compress and radially expand to tightly engage the surface of the cavity  502  and the catheter  400 . The counterbore  510  can be sized to receive a portion of a head  516  of the ferrule  514  to minimize outwardly protruding features on the port  100 ,  200 . The gasket  512  can be a singular component or can be composed of multiple components, as desired. 
     For ease of installation, the inner diameter of the gasket  512  can be larger than an outer diameter of the catheter  400 . Further, the proximal end  406  of the catheter  400  can be reinforced to have a higher hoop strength to withstand the compressive force generated by the gasket  512 . If desired, the ferrule  514  and/or cavity  502  can include a torque limiting tool to prevent overtightening and the possible resulting damage to the catheter  400 . 
     In an alternative example, as shown in  FIG. 39 , the cavity  502  can include a catheter counterbore  518  at the interior end  504  thereof. The catheter counterbore  518  has a diameter sized to receive a portion of the proximal end  406  of the catheter  400  therein, but also sized to be smaller than the gasket  512 . With this configuration, the end of the catheter  400  is not compressed by the gasket  512  during tightening and therefore possible crushing of the end is prevented. 
     In another example, as shown in  FIG. 40 , the assembly  500  can utilize a snap-fit connection rather than a threaded connection as described above with respect to  FIGS. 2, 4, and 39 . Pursuant to this, the cavity  502  can include an annular snap-fit recess  520  having a radially outward stop surface  522  and a ferrule  524  can include an outwardly projecting annular prong  526 . So configured, the ferrule  524 , extending around the catheter  400 , can be inserted into the cavity  502  until the prong  526  is biased into the recess  520  by the resiliency of the ferrule  524  and/or the catheter  400 . The prong  526  engages the stop surface  522  of the recess  520 , preventing removal of the ferrule  524 . Further, the recess  520  can be located within the cavity  502  and the gasket  512  can be sized to provide an optimal amount of compression to result in a fluid tight seal without overly compressing the catheter  400 . Although the recess  520  and prong  526  are described as annular, discrete portions that can be aligned during insertion is within the scope of this disclosure. 
     In another example as shown in  FIG. 41 , the assembly  500  can utilize a luer lock connection rather than a threaded or snap-fit connection as described above. Pursuant to this, the cavity  502  can include a plurality of radial recesses  528  with outwardly extending openings  530 . A ferrule  532  of this form can include a plurality of radial tabs  534  that are positioned to align with the openings  530 . For example, the tabs  534  and openings  530  can be symmetrically disposed around the ferrule  532  and cavity  502  respectively. During assembly, a clinician can align the tabs  534  with the openings  530 , insert the ferrule  532  into the cavity  502  until the tabs  534  align with the radial recesses  528 , and turn the ferrule  532  a predetermined amount, such as a quarter turn, to lock the ferrule  532  to the port  100 ,  200 . By one approach, the radial recesses  528  can be sized to frictionally engage the tabs  534 . Further, the radial recesses  528  can be located within the cavity  502  and the gasket  512  can be sized to provide an optimal amount of compression to result in a fluid tight seal without overly compressing the catheter  400 . 
     In another example, as shown in  FIG. 42 , the port  100 ,  200  can include an outwardly projecting tube  536  having a passage  538  extending from the delivery opening  110 ,  210  of the chamber  108 ,  208 . In a first form, the tube  536  can have an outer diameter that is equal to or smaller than an inner diameter of the catheter proximal end  406  so that the proximal end  406  can be inserted over and around the tube  536 . To secure the catheter  400  to the tube  536 , a spring  540 , which can be made of metal, such as nitinol, for example, having a resting state compressing the catheter  400 , can be twisted to loosen the spring  540  to allow the catheter proximal end  406  to be inserted onto the tube  536  and released to compress and secure the catheter  400  to the port  100 ,  200 . If desired, a clinician can utilize a tool to engage the spring  540  to easily loosen the windings thereof during assembly. 
     In another example, as shown in  FIG. 43 , the outwardly projecting tube  536  can include a backstop  542  extending around an intermediate portion thereof and the catheter proximal end  406  can have a press-fit ring  544  mounted thereto. As shown, the catheter proximal end  406  can have an expanded diameter to secure within the ring  544  and an interior opening  546  of the ring  544  can be sized to have a press-fit engagement with the tube  536 . So configured, a clinician can simply align the opening  546  with the tube  536  and press the ring  544  until the ring  544  abuts the backstop  542 . 
     In another example, as shown in  FIG. 44 , the port  100 ,  200  can include an annular wall  548  encircling the tube  536 . The assembly  500  of this form, can further include an o-ring  550  having an inner diameter smaller than an outer diameter of the catheter proximal end  406  such that the o-ring  550  provides a compressive force on the catheter  400  when mounted therearound. During assembly, the o-ring  550  can be shifted longitudinally along the catheter  400  so that the proximal end  406  can be fully inserted between the tube  536  and wall  548 . Thereafter, the o-ring  550  can be stretched or rolled onto the wall  548  to provide a compressive force through the wall  548  to the catheter  400  and tube  536 . By one approach, the inner diameter of the wall  548  can be generally equal, within 1 mm, of an outer diameter of the catheter  400  so that the catheter  400  is tightly received in the annular space between the wall  548  and tube  536 . The o-ring  550  can be formed from rubber or any suitable elastomer, for example. 
     In another example, as shown in  FIG. 45 , the assembly  500  of this form can utilize a clamping member  552  to secure the catheter proximal end  406  to the tube  536 . The clamping member  552  can include upper and lower portions  554 ,  556  that are movable with respect to one another to be clamped around the catheter proximal end  406  and the tube  536  during assembly. As shown, the catheter proximal end  406  and the tube  536  can be axially aligned in a lap joint connection so that the ends thereof abut one another and the clamping member  552  can be secured thereover to provide a fluid tight seal. The upper and lower portions  554 ,  556  can be secured together by any suitable mechanism, including snap-fit, crimping, an attachment member, and so forth. 
     In another example, as shown in  FIG. 46 , the port  100 ,  200  can include an annular wall  558  encircling the tube  536  creating an annular catheter reception space  560  between the wall  558  and tube  536 . The catheter proximal end  406  of this form can have an enlarged outer diameter as compared to the main body of the catheter  400 , such that the proximal end  406  has greater hoop strength and can withstand greater compressive forces during assembly. Pursuant to this, the reception space  560  can be sized to receive the catheter proximal end  406  therein in a compressive, press-fit configuration to secure the catheter  400  to the port  100 ,  200  and form a fluid tight seal between the tube  536  and catheter  400 . 
     In another example, as shown in  FIG. 47 , the port  100 ,  200  can include a pre-connected assembly  562  including a flexible tube  564  secured to the body  102 ,  202  and fluidly connected to the delivery opening  110 ,  210  and a connector  566 . The connector  566  includes a central stem  568  and surrounding housing  570  that define an annular catheter reception space  572  therebetween. So configured, during assembly a clinician can insert the catheter proximal end  406  into the reception space  572  to fluidly couple the catheter  400  to the port  100 ,  200 . The coupling can utilize a press-fit as described above, or can utilize an o-ring  574  on the housing  570  in similar configuration as described above with respect to  FIG. 43  to provide a compressive force on the catheter  400  and stem  568 . 
     In another example, as shown in  FIG. 48 , the port  100 ,  200  can include a connection member  576  having a base  578  and an outwardly projecting stem  580 , which can be made of metal, such as titanium, for example, The connection member  576  includes a passage  582  therethrough that is fluidly coupled to the delivery opening  110 ,  210 . As shown, the stem  580  can include barbs  583  that extend outwardly from an intermediate portion thereof to engage and retain the catheter proximal end  406  after assembly. The assembly  500  of this form can further include a plastic housing  584  extending around the connection member  576  to engage the outer jacket  414  of the catheter  400 . So configured, a clinician can insert the catheter proximal end  406  over the stem  580  until the catheter  400  abuts the base  578 . The barbs  583  and housing  584  provide a compressive force on the catheter  400  to secure the catheter  400  to the port  100 ,  200 . 
     In another example, as shown in  FIG. 49 , the tube  536  can have an outer diameter that is larger than an inner diameter of the catheter  400  and the catheter proximal end  406  can be flexible to be stretched over the tube  536  during assembly. By one approach, the tube  536  can include a radial lip or barb  586  extending therearound to retain the stretched catheter end  406  on the tube  536 . Given the flexible nature of the catheter proximal end  406  of this form, the assembly  500  can further include a rigid or resilient sleeve  588  that extends along the flexible length of the catheter  400  to prevent the flexible portion from becoming kinked. 
     As is understood, implantation of a catheter into the intrathecal space of a patient can be achieved using a stylet. As shown in  FIG. 50 , the port  100 ,  200  can include a side septum assembly  600  so that a stylet  602  can be pre-loaded and provided with the port  100 ,  200 . The side septum assembly  600  includes a radial cavity  604  extending between the chamber  108 ,  208  and the exterior  114 ,  214  of the body  102 ,  202  and a septum  606  received within the cavity  604 . In the illustrated form, the cavity  604  includes an outwardly projecting recess  608  to receive a flange portion  610  of the septum  606  to prevent or minimize movement of the septum  606  while the style  602  is moved therethrough. The side septum assembly  600  can advantageously be located across the chamber  108 ,  208  from the delivery opening  110 ,  210  so that the stylet  602  can be easily threaded therethrough. Further, the side septum assembly  600  can be utilized with any of the catheter connection assemblies  500  described above. 
     One example method for implanting the fluid delivery systems described herein includes selecting a suitable bony structure of a patient for implantation of the port  100 ,  200  and securing the port  100 ,  200  to the bony structure by any suitable method. The method can further include a clinician placing the distal end  408  of the catheter  400  in the intrathecal space of a patient, utilizing the features and properties of the catheter  400  to tunnel the proximal end  406  of the catheter  400  under the skin within the intrathecal space to the subcutaneously implanted port  100 ,  200 , and connecting the catheter  400  to the port  100 ,  200  via any of the connection assemblies  500  described herein. 
     After the port  100 ,  200  and catheter  400  have been implanted and coupled together, a clinician can utilize the fluid delivery system to sample cerebrospinal fluid for diagnostic purposes or can utilize the system to deliver a composition (e.g., a dose of a therapeutic agent) to the intrathecal space of the patient. The clinician can locate the subcutaneous port  100 ,  200  using any of the above-described features. After the port  100 ,  200 , and the septum  106 ,  206  thereof, is located a clinician can use a Huber needle attached to a standard syringe containing the composition and, manually, using a standard syringe pump, or using Pulsar auto-injector pump, slowly inject the composition into the chamber  108 ,  210  to dispense the composition through the outlets  418 ,  428  of the catheter  400  into the intrathecal space of the patient. The medication can be delivered as bolus or per infusion algorithm from the Pulsar pump using the Pulsar auto-injector pump. In some cases where the composition comprises a therapeutic agent, an approved dosing regimen of the therapeutic agent may require removal of cerebrospinal fluid before injection of the therapeutic agent, which can be done manually, using a standard syringe pump, or using Pulsar auto injector pump from the port  100 ,  200  via the non-coring Huber needle attached to a syringe. The syringe can also be loaded to a Pulsar auto injector pump. 
     The port  100 ,  200 , and the chamber  108 ,  208  thereof, can be configured so that there is minimal dead volume for the composition. For example, the dead volume of the port  100 ,  200  can be between about 1.0 mL and no dead volume, and, in one form, about 0.5 mL. 
     In another example, as shown in  FIG. 51 , the chamber  108 ,  208  of the port  100 ,  200  can be impregnated or pre-loaded with one or more dosages  650  of a therapeutic agent. A clinician can dispense one of the doses  650  by applying pressure to the septum  106 ,  206  or other movable portion of the port  100 ,  200  to force the dose  650  through the delivery opening  110 ,  210  and into the catheter  400 . If more than one dose  650  is provided, the dosages  650  can be separated by movable doors  652  extending across the chamber  108 ,  208 . The doors  652  can be metallic and be selectively and non-invasively moved by a clinician using an external device  654  having one or more magnets therein. 
     The fluid delivery systems described herein can further be provided as a set, which can include an implantation kit/introducer, anchoring components for the catheter  400 , and/or a facial anchor. Further, if desired, a filter can be provided in the catheter, delivery opening  110 ,  210 , or chamber  108 ,  208 . 
     The device described herein is suitable for administering any fluid composition, such as a pharmaceutical composition comprising one or more therapeutic agents, to a subject. Indeed, the device of the disclosure optionally comprises one or more dosages of a therapeutic agent, such as a therapeutic agent suitable for treating (in whole or in part) a disorder, infection, or injury of the central nervous system or spine. Disorders associated with aspects of the central nervous system or spine include, but are not limited to, spinal muscular atrophy, survival motor neuron deficiency, ankylosing spondylitis, spinal tumors, bipolar disorder, encephalitis, depression, epilepsy, Dravet Syndrome, meningitis, multiple sclerosis, myeopathy, Angelman&#39;s Syndrome, CNS lymphoma, Leptomeningeal cancer, Friedreich&#39;s Ataxia, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), cerebral amyloid angiopathy (CAA), amyloid congophilic angiopathy (ACA), and secondary malignant neoplasms (SMN), or neurodegenerative disorders, e.g., Tau protein-related disorders including Alzheimer&#39;s disease, Huntington&#39;s disease, alpha-synuclei-related disorders including Parkinson&#39;s disease, amyotrophic lateral sclerosis (ALS) including superoxide dismutase 1-related ALS, progressive spranuclear palsy, frontotemporal dementia, and Tourette&#39;s syndrome. Infections of the CNS include, but are not limited to, viral meningitis, fungal meningitis, epidural infection, viral encephalitis, and neurosyphilis. 
     Any therapeutic agent may be used in the context of the disclosure. Exemplary therapeutic agents include, e.g., nucleic acids, protein therapeutics, cell therapies, and small molecule therapeutics. Examples of protein therapeutics include antibody-based therapeutics, such as antibodies, antibody fragments, or antibody-like protein products that include binding regions of antibodies (e.g., scFv, diabodies, antibody mimetics, and the like). The antibody-based therapeutic may target, e.g., amyloid plaques, tau proteins, cancer antigens, or abnormal alpha-synuclein. Examples of protein therapeutics also include, but are not limited to, hormones, enzymes (e.g., lysosomal enzymes, such as alpha-L-iduronidase, N-acetylgalactosamine-4-sulfatase, or beta-glucuronidase), growth factors (e.g., fibroblast growth factor (FGF) or neurotrophins or neurotrophic factors, such as glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), or nerve growth factor (NGF)), blood factors, bone morphogenetic proteins, interferons, interleukins, and thrombolytics. Examples of cell-based therapies include, but are not limited to, stem cell therapeutics and immune cells (including modified immune cells, such as CAR T cells). Suitable small molecule therapeutics include, but are not limited to, analgesics, ion channel blockers, anti-convulsive agents, antibiotics or antiviral agents, anti-inflammatories, anticoagulants, chemotherapeutic, anti-depressants, anti-anxiety agents, steroids, and the like. In various aspects, the therapeutic agent is baclofen, morphine, bupivacaine hydrochloride, clonidine hydrochloride, gabapentin, idursulfase, cytarabine, methotrexate, a corticosteroid, edavarone-conjugate, conotoxin, abomorphine, prednisolone hemisuccinate sodium, carbidopa/levodopa, tetrabenazine, benzodiazepines, such as diazepam and midazolam, alphaxalone or other derivative, cyclophosphamide, idursulfase (Elaprase®), iduronidase (Aldurazyme®), topotecan, buslfan, opmaveloxolone, epicatechin, methylprednisolone, frataxin replacement, reservatrol, nicontinamide, AT-010 (RNA that induces splicing modulation in the mature amyloid precursor protein mRNA), Cerebril™, an anti-Aβ antibody, elenbecestat, a corticosteroid, or nusinersen (Spinraza®), or combinations thereof. 
     In various aspects, the therapeutic agent is a nucleic acid, including DNA or RNA, which may be single stranded or double stranded and which may be modified or unmodified. Suitable nucleic acid-based therapeutic agents include, but are not limited to, antisense oligonucleotides, ribozymes, miRNA, siRNA, and shRNA. Optionally, the nucleic acid targets a gene selected from the group consisting of APP, MAPT, SOD1, BACE1, CASP3, TGM2, TARDBP, ADRB1, CAMK2A, CBLN1, CDK5R1, GABRA1, MAPK10, NOS1, NPTX2, NRGN, NTS, PDCD2, PDE4D, PENK, SYT1, TTR, FUS, LRDD, CYBA, ATF3, CASP2, HRK, C1QBP, BNIP3, MAPK8, MAPK14, Rac1, GSK3B, P2RX7, TRPM2, PARG, CD38, STEAP4, BMP2, GJA1, TYROBP, CTGF, ANXA2, DUOX1, RTP801, RTP801L, NOX4, NOX1, NOX2 (gp91pho, CYBB), NOX5, DUOX2, NOXO1, NOXO2 (p47phox, NCF1), NOXA1, NOXA2 (p67phox, NCF2), p53 (TP53), HTRA2, KEAP1, SHC1, ZNHIT1, LGALS3, SESN2, SOX9, ASPP1, CTSD, CAPNS1, FAS, FASLG, CAPN1, FADD, CASP1, CASP9, p75NTR, PARK2, HTT (with expanded repeats), NogoA, MAG, OMGP, NgR1, PDE4, BCAN, NCAN, PTPRZ1, TNC, NRP1, NRP2, PLXNA1, PLXNA2, PLXNB1, PLXNC1, TROY, LRRC1, ROCK1, LimK1, LimK2, CFL1, KCNC4, KCNE3, NAT8L, FKBP1A, FKBP4, LRRK2, DYRK1A, AKAP13, UBE2K, WDR33, MYCBP2, SEPHS1, HMGB1, HMGB2, TRPM7, BECN1, THEM4, SLC4A7, MMP9, SLC11A2, ATXN3, ATXN1, ATXN7, PRNP, EFNB3, EPHA4, EFNAS, EPHA7 and EFNB2, such that gene expression or function is modified. 
     In some embodiments, the therapeutic agent is an oligonucleotide comprising at least one modified nucleotide, optionally a modified nucleotide that reduces binding to cerebral spinal fluid (CSF) proteins. In various embodiments, the modified nucleotide includes a substituent at the 2′-position, such as a 2′-O-2-methoxyethyl (“2′-MOE”) group, as shown below, wherein X is O or S. 
     
       
         
         
             
             
         
       
     
     Oligonucleotides comprising a 2′-MOE modification can distribute rapidly in central nervous system tissues. Oligonucleotides comprising such modifications exhibit extended half-lives in CSF and central nervous system tissues, which can result in less frequent dose administration. 
     In some cases, the modified nucleotide can include a 2,4-constrained group, such as a constrained 2-O-ethyl (“cEt”) group. In various cases, the cEt group can have S-stereochemistry (“S-cEt”), as shown below, wherein X is 0 or S. 
     
       
         
         
             
             
         
       
     
     Nucleic acids modified with a constrained ethyl group, such as S-cEt, can exhibit enhanced thermal stability, good potency, and a good therapeutic profile. 
     Optionally, the nucleic acid encodes a beneficial protein that, e.g., replaces an absent or defective protein, or encodes a cytotoxic protein that achieves a therapeutic effect, such as cancer cell death. Any of the protein-based therapeutics described herein may be delivered to a subject via delivery of a nucleic acid encoding the protein under conditions which allow expression in vivo. For example, in various embodiments, the nucleic acid encodes a neurotrophic factor such as, but not limited to, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurotrophin-6 (NT-6), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), the fibroblast growth factor family (e.g., FGF 1-15), leukemia inhibitory factor (LIF), certain members of the insulin-like growth factor family (e.g., IGF-1), a neurturin, persephin, a bone morphogenic protein (BMPs), an immunophilin, a member of the transforming growth factor (TGF) family of growth factors, a neuregulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor family (e.g. VEGF 165), follistatin, or Hifl, or combinations thereof. 
     In various aspects, the nucleic acid is present in a viral vector. Any viral vector appropriate for delivering a therapeutic agent to a human subject may be used. Examples of viral vectors include, e.g., herpes simplex virus (HSV) vectors, adenovirus (Ad) vectors, parvoviral-based vectors (e.g., adeno-associated viral vectors), chimeric Ad-AAV vectors, and retroviral vectors (including lentiviral vectors, HIV vectors). Any of these gene transfer vectors can be prepared using standard recombinant DNA techniques described in, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 2d edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1989), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley &amp; Sons, New York, N.Y. (1994). 
     In some embodiments, the viral vector is an AAV vector. AAV vectors used for administration of a therapeutic nucleic acid typically have approximately 96% of the parental genome deleted, such that only the terminal repeats (ITRs), which contain recognition signals for DNA replication and packaging, remain. Delivering the AAV rep protein enables integration of the AAV vector comprising AAV ITRs into a specific region of genome, if desired. AAV vectors are useful for delivering payload to the central nervous system due, at least in part, to their safety profile, long-term gene expression, and ability to infect both dividing and quiescent cells, including neurons. Multiple serotypes of AAV exist and offer varied tissue tropism. Known serotypes include, for example, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 and AAV11. AAV vectors may be engineered to alter the virus native tropism or improve infection by modifying the viral capsid or packaging the genome of one serotype into the capsid of a different serotype. AAV vectors have been used to deliver a number of transgenes to treat a variety of diseases, including ASP to treat Canavan disease; CLN2 to treat Late infantile neuronal ceroid lipofuscinosis; SGSH to treat mucopolysaccharidosis IIIA; NAGLU to treat mucopolysaccharidosis IIIB; ARSA to treat metachromatic leukodystrophy; GAD, AADC, NTN, GDNF, AADC to treat Parkinson®; and NGF to treat Alzheimer®. See, e.g., Hocquemiller et al., Hum Gene Ther., 27(7), 478-496 (2016), hereby incorporated by reference. The genomic sequences of AAV, as well as the sequences of the ITRs, Rep proteins, and capsid subunits are known in the art. See, e.g., International Patent Publications Nos. WO 00/28061, WO 99/61601, WO 98/11244; as well as U.S. Pat. No. 6,156,303, Srivistava et al. (1983) J Virol. 45:555; Chiorini et al (1998) J Virol. 71:6823; Xiao et al (1999) J Virol. 73:3994; Shade et al (1986) J Virol. 58:921; and Gao et al (2002) Proc. Nat. Acad. Sci. USA 99:11854. 
     In various embodiments, the device is used to deliver one or more gene editing agents to a subject, such as the clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (Cas) system. CRISPR-Cas and similar gene targeting systems are in the art with reagents and protocols readily available. See, e.g., Maliet al., Science, 339(6121), 823-826 (2013); and Hsu et al., Cell, 157.6: 1262-1278 (2014). Exemplary genome editing protocols are described in Doudna and Mali, “CRISPR-Cas: A Laboratory Manual” (2016) (CSHL Press, ISBN: 978-1-621821-30-4) and Ran et al., Nature Protocols 8(11): 2281-2308 (2013). The CRISPR/Cas system comprises a CRIPSR/Cas nuclease (typically Cas9) and guide RNA (or crRNA-tracrRNA) comprising a short nucleotide targeting sequence that directs the nuclease to a genome location of interest. The guide RNA(s) and coding sequence for the Cas nuclease, optionally packaged into viral vectors, can be delivered to the CSF via the device of the disclosure. The CRISPR/Cas system is further described in, e.g., U.S. Patent Publication Nos. 2018/0223311. 
     In various aspects, the disclosure provides a method of treating Huntington&#39;s disease, Spinal Muscular Atrophy (SMA), survival motor neuron (SMN) deficiency, amyotrophic lateral sclerosis (ALS) (including superoxide dismutase 1 (SOD1)-related ALS), Angelman&#39;s syndrome, Dravet syndrome, Alzheimer&#39;s disease and other tau protein-related disorders, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), alpha-synuclei-related disorders including Parkinson&#39;s Disease, central nervous system (CNS) lymphoma, leptomeningeal cancer, Friedreich&#39;s Ataxia, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), cerebral amyloid angiopathy (CAA), amyloid congophilic angiopathy (ACA), or secondary malignant neoplasms (SMN). The method comprises implanting a fluid delivery system in the patient such that a catheter of the fluid delivery system is disposed within the patient&#39;s intrathecal space, the catheter characterized by a catheter body having an outer diameter in the range of about 0.25 mm to 1.5 mm and a composite, kink-resistant structure. The fluid delivery system further comprises a grommet having a sleeve portion extending around the catheter body and a flange portion to engage the dura of the patient over a catheter opening therein. The method further comprises releasing a therapeutic agent (such as any one or more of the therapeutic agents described above) via the catheter into the intrathecal space, such that the disorder is treated. 
     It will be appreciated that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention. Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments. The same reference numbers may be used to describe like or similar parts. Further, while several examples have been disclosed herein, any features from any examples may be combined with or replaced by other features from other examples. Moreover, while several examples have been disclosed herein, changes may be made to the disclosed examples within departing from the scope of the claims. 
     Those skilled in the art will recognize that a wide variety of modifications, alterations, and combinations can be made with respect to the above described embodiments without departing from the scope of the invention, and that such modifications, alterations, and combinations are to be viewed as being within the ambit of the inventive concept.