Patent Publication Number: US-2020275948-A1

Title: Drug delivery systems and methods

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to U.S. Provisional Application No. 62/437,168 filed on Dec. 21, 2016, which is hereby incorporated by reference in its entirety. 
    
    
     FIELD 
     Systems and methods are disclosed herein for delivering a drug to a subject (e.g., via intrathecal delivery into the cerebrospinal fluid (CSF) or subarachnoid space of the subject&#39;s brain or spine). 
     BACKGROUND 
     There are many instances in which it may be desirable to deliver a drug to a patient. The term “drug” as used herein refers to any functional agent that can be delivered to a human or animal subject, including hormones, stem cells, gene therapies, chemicals, compounds, small and large molecules, dyes, antibodies, viruses, therapeutic agents, etc. 
     Delivery of the drug can be done in a systemic manner, or can be targeted to a particular location or a particular distribution pattern. Targeted drug delivery can be challenging, however, as there are many instances in which the intended delivery target is not accessible, or not accessible in a minimally-invasive manner. 
     The natural physiology of the patient can also present drug delivery challenges. For example, achieving a desired or optimal drug distribution via intrathecal delivery can be difficult, at least in part due to the natural flow of CSF within the patient, which tends to be oscillatory and pulsatile with little net flow. Traditional techniques which involve delivering a large quantity of a drug to the intrathecal space and relying on natural diffusion to distribute the drug are inefficient and may be harmful to the patient. 
     There is a continual need for improved drug delivery systems and methods. 
     SUMMARY 
     Drug delivery systems and methods are disclosed herein. In some embodiments, a drug delivery system can be configured to deliver a drug to a patient in coordination with a physiological parameter of the patient (e.g., the patient&#39;s natural cerebrospinal fluid (CSF) pulsation or the patient&#39;s heart or respiration rate). In some embodiments, a drug delivery system can be configured to use a combination of infusion and aspiration to control delivery of a drug to a patient. Catheters, controllers, and other components for use in the above systems are also disclosed, as are various methods of using such systems. 
     In some embodiments, a drug delivery device can include an elongate body having a fluid lumen formed therein; and a fluid port formed in the delivery device, the fluid port being defined by a helical slit formed in a wall of the delivery device. 
     The helical slit can extend from an interior surface of the body to an exterior surface of the body. The helical slit can act as a fluid communication path between an interior of the fluid lumen and an exterior of the delivery device. The helical slit can be formed through an exterior wall of the delivery device. The helical slit can be formed in a sidewall of a reduced-diameter portion of the delivery device. The helical slit can be formed in a sidewall of an inner tube that projects from a distal end of the body. The delivery device can include an atraumatic distal tip defined by a substantially spherical bulb. The delivery device can include a second, distal-facing fluid port. The delivery device can include a tapered transition between a larger diameter proximal portion of the delivery device and a reduced diameter distal portion of the delivery device. The tapered transition can be at least one of conical, convex, and concave. The delivery device can be or can include a catheter. The delivery device can be or can include a needle. The delivery device can include an inflatable member disposed at a distal end of the delivery device. The inflatable member can be deployable from within a sharpened distal tip of the device. The inflatable member can include a fluid port therein. The fluid port of the inflatable member can include a helical slit. 
     In some embodiments, a drug delivery device can include an elongate body having a fluid lumen therein and a fluid port through which fluid can move between an interior of the fluid lumen and a location exterior to the delivery device; wherein at least a portion of the fluid lumen is helically-shaped. 
     The helically-shaped portion of the fluid lumen can be adjacent to the fluid port. The helically-shaped portion of the fluid lumen can include a tubular passage that defines a plurality of looped coils. 
     In some embodiments, a drug delivery device can include a needle having a sharpened distal tip; and an inflatable member selectively deployable from a distal end of the sharpened tip, the inflatable member having a fluid port formed therein; wherein the fluid port comprises a helical slit. 
     In some embodiments, a patient-specific infusion method can include determining a total CSF volume of a patient; aspirating a volume of CSF from the patient based on the determined total CSF volume of the patient; and infusing a drug into an intrathecal space of the patient. 
     The method can include, after infusing the drug, infusing the aspirated CSF of the patient to push the drug in a desired direction within the intrathecal space. The total CSF volume can be determined from a pre-operative image of the patient&#39;s central nervous system. The aspirated volume of CSF can be in the range of about 1% to about 20% of the total CSF volume of the patient. The drug can be infused while the volume of CSF is aspirated. 
     In some embodiments, a drug delivery method can include inserting a needle into an intrathecal space of a patient; inserting a fluid delivery catheter through the needle and into the intrathecal space; infusing a drug through the catheter and into the intrathecal space; and infusing a chaser through the needle behind the drug to push the drug through the intrathecal space. 
     The chaser can include at least one of a drug, a buffer, artificial CSF, natural CSF previously aspirated from the patient, and saline. The chaser can include previously-aspirated CSF. The CSF can be aspirated and infused using the same syringe in a closed system. The needle can protrude into the intrathecal space by a distance in the range of 0 cm to 1 cm. The catheter can protrude from the needle by a distance in the range of 0 cm to 1 cm. 
     In some embodiments, a drug delivery system includes a catheter having at least one fluid lumen; a pump configured to infuse fluid through the catheter; a sensor configured to measure a physiological parameter of a patient; and a controller that controls the pump to coordinate infusion of a drug through the catheter with the physiological parameter measured by the sensor. 
     The controller can synchronize infusion frequency with a frequency of a patient&#39;s natural intrathecal pulsation as measured by the sensor. The controller can synchronize infusion phase with a phase of a patient&#39;s natural intrathecal pulsation as measured by the sensor. The controller can establish a sinusoidal approximation of the patient&#39;s natural intrathecal pulsation as measured by the sensor. The controller can synchronize infusions with the ascending wave of the sinusoidal approximation. The controller can synchronize infusions with the descending wave of the sinusoidal approximation. The sensor can be configured to measure intrathecal pressure. The sensor can include a first sensor configured to measure intrathecal pressure and a second sensor configured to measure heart rate. The controller can be operable in a learning mode in which no infusion is performed and the controller establishes a correlation between heart rate and intrathecal pressure based on the output of the first and second sensors; and an infusion mode in which the controller coordinates infusion of the drug through the catheter with the intrathecal pulsation of the patient based on the output of the second sensor. The system can include an implantable infusion port in fluid communication with the catheter and an extracorporeal injector configured to mate with the infusion port. The catheter can include first and second fluid lumens. The controller can be configured to control the pump to alternately aspirate fluid through the first fluid lumen and infuse fluid through the second fluid lumen in coordination with the physiological parameter measured by the sensor. The sensor can be configured to measure at least one of heart rate, intrathecal pressure, intrathecal pulsation rate, respiration rate, lung capacity, chest expansion, chest contraction, intrathoracic pressure, and intraabdominal pressure. 
     In some embodiments, a method of delivering a drug to a patient includes inserting a catheter into an intrathecal space of the patient; measuring a physiological parameter of the patient using a sensor; and with a controller, controlling a pump to coordinate infusion of a drug through the catheter with the physiological parameter measured by the sensor. 
     The method can include synchronizing infusion frequency with a frequency of the patient&#39;s natural intrathecal pulsation as measured by the sensor. The method can include synchronizing infusion phase with a phase of the patient&#39;s natural intrathecal pulsation as measured by the sensor. The method can include establishing a sinusoidal approximation of the patient&#39;s natural intrathecal pulsation as measured by the sensor and synchronizing infusions with an ascending wave of the sinusoidal approximation. The method can include establishing a sinusoidal approximation of the patient&#39;s natural intrathecal pulsation as measured by the sensor and synchronizing infusions with a descending wave of the sinusoidal approximation. The sensor can be configured to measure intrathecal pressure. The sensor can include a first sensor configured to measure intrathecal pressure and a second sensor configured to measure heart rate. The method can include establishing a correlation between heart rate and intrathecal pressure based on the output of the first and second sensors when no infusion is performed; and coordinating infusion of the drug through the catheter with the intrathecal pulsation of the patient based on the output of the second sensor. The catheter can include first and second fluid lumens, and the method can include controlling the pump to alternately aspirate fluid through the first fluid lumen and infuse fluid through the second fluid lumen in coordination with the physiological parameter measured by the sensor. The sensor can be configured to measure at least one of heart rate, intrathecal pressure, intrathecal pulsation rate, respiration rate, lung capacity, chest expansion, chest contraction, intrathoracic pressure, and intraabdominal pressure. The catheter can be inserted such that it extends along the spinal cord of the patient with at least a portion of the catheter being disposed in the cervical region of the patient&#39;s spine and at least a portion of the catheter being disposed in the lumbar region of the patient&#39;s spine. The method can include delivering a plurality of different drugs through the catheter, each of the drugs being delivered through a respective fluid lumen of the catheter. The method can include, with the controller, controlling the pump to aspirate fluid through the catheter. The catheter can include a plurality of outlet ports spaced in a cranial-caudal direction along the length of the catheter and the method can include infusing a drug through a first port of the catheter and aspirating fluid through a second port of the catheter, the second port being cranial to the first port. The drug can be infused through a port of the catheter disposed in the cervical region of the patient&#39;s spine to propel the infused drug into the cranial space. The method can include aspirating a volume of CSF from the patient; infusing a drug through a first, proximal port of the catheter while aspirating CSF through a second, distal port of the catheter to form a bolus of drug between the first and second ports; and infusing the previously-extracted CSF at a location proximal to the bolus to urge the bolus in a distal direction. The volume of CSF aspirated from the patient can be about 10% by volume of the patient&#39;s total CSF. The catheter can be inserted through a percutaneous lumbar puncture in the patient. The infusion can include alternating between infusing a first volume of the drug and aspirating a second volume of the drug, the second volume being less than the first volume. The drug can be delivered to a target region, the target region being at least one of an intrathecal space of the patient, a subpial region of the patient, a cerebellum of the patient, a dentate nucleus of the patient, a dorsal root ganglion of the patient, and a motor neuron of the patient. The drug can include at least one of an antisense oligonucleotide, a stereopure nucleic acid, a virus, adeno-associated virus (AAV), non-viral gene therapy, vexosomes, and liposomes. The method can include at least one of performing gene therapy by delivering the drug, performing gene editing by delivering the drug, performing gene switching by delivering the drug, and performing non-viral gene therapy by delivering the drug. The method can include determining a total CSF volume of the patient and tailoring the infusion based on the total CSF volume. 
     In some embodiments, a method of delivering a drug to a patient includes inserting a catheter into an intrathecal space of the patient; with a controller, controlling a pump to infuse a drug through the catheter; with the controller, controlling the pump to aspirate fluid through the catheter; and controlling said infusion and said aspiration to target delivery of the drug to a target site within the patient. 
     The infusion can override the natural CSF pulsation of the patient to urge the drug towards the target site. The infusion can coordinate with the natural CSF pulsation of the patient to urge the drug towards the target site. The infusion can include delivering a bolus of the drug and then performing pulsatile delivery of a fluid behind the bolus to urge the bolus towards the target site. The fluid can include at least one of a drug, a buffer solution, and CSF aspirated from the patient through the catheter. At least a portion of the catheter can be disposed in the target region. At least one of the infusion and the aspiration can be coordinated with a physiological parameter of the patient. The physiological parameter can be at least one of heart rate, intrathecal pressure, intrathecal pulsation rate, respiration rate, lung capacity, chest expansion, chest contraction, intrathoracic pressure, and intraabdominal pressure. The catheter can include first and second fluid lumens, and the method can include controlling the pump to alternately aspirate fluid through the first fluid lumen and infuse fluid through the second fluid lumen. The catheter can be inserted such that it extends along the spinal cord of the patient with at least a portion of the catheter being disposed in the cervical region of the patient&#39;s spine and at least a portion of the catheter being disposed in the lumbar region of the patient&#39;s spine. The method can include aspirating a volume of CSF from the patient; infusing a drug through a first, proximal port of the catheter while aspirating CSF through a second, distal port of the catheter to form a bolus of drug between the first and second ports; and infusing the previously-extracted CSF at a location proximal to the bolus to urge the bolus in a distal direction. The method can include alternating between infusing a first volume of the drug and aspirating a second volume of the drug, the second volume being less than the first volume. The target site can be at least one of an intrathecal space of the patient, a subpial region of the patient, a cerebellum of the patient, a dentate nucleus of the patient, a dorsal root ganglion of the patient, and a motor neuron of the patient. The drug can include at least one of an antisense oligonucleotide, a stereopure nucleic acid, a virus, adeno-associated virus (AAV), non-viral gene therapy, vexosomes, and liposomes. The method can include at least one of performing gene therapy by delivering the drug, performing gene editing by delivering the drug, performing gene switching by delivering the drug, and performing non-viral gene therapy by delivering the drug. The method can include determining a total CSF volume of the patient and tailoring the infusion and/or the aspiration based on the total CSF volume. 
     In some embodiments, a drug delivery catheter includes a tip having a first fluid lumen that extends to a first fluid port, a second fluid lumen that extends to a second fluid port, and a guidewire lumen; a hub; and a body having a first fluid tube that defines a first fluid lumen that is in fluid communication with the first fluid lumen of the tip, a second fluid tube that defines a second fluid lumen that is in fluid communication with the second fluid lumen of the tip, a guidewire having a distal end disposed within the guidewire lumen of the tip, and a sheath that defines at least one interior channel in which the guidewire and the first and second fluid tubes are disposed, wherein the sheath extends from a distal end of the hub to a proximal end of the tip. 
     The tip can have a tapered distal end. The first and second fluid ports can be offset from a central longitudinal axis of the tip. At least one of the first and second fluid ports can be aimed perpendicular to, or at an oblique angle with respect to, the central longitudinal axis of the tip. The first and second fluid tubes can extend uninterrupted through the hub. The first and second fluid tubes can terminate within the hub at respective connectors to which proximal extension tubes can be selectively coupled. The guidewire can extend uninterrupted through the hub. The first and second fluid tubes can have respective fluid connectors at proximal ends thereof. At least one of the first and second fluid tubes can be formed from fused silica. At least one of the first and second fluid tubes can be coated in shrink tubing. The sheath can be formed form polyurethane. The sheath can include an opening formed therein in fluid communication with a fluid port of at least one of the first and second fluid tubes. At least one of the first and second ports can have a helical interior. At least one of the first and second ports can have an interior that tapers towards the distal end of the port. The first fluid port can be proximal to the second fluid port. The catheter can include an auger rotatably mounted within the catheter. The catheter can include a piezoelectric transducer disposed within the catheter. 
     In some embodiments, a percutaneous needle device includes an elongate shaft that defines at least one lumen therein; a sensor disposed at a distal end of the elongate shaft; a display mounted to the elongate shaft configured to display an output of the sensor; and a connector disposed at a proximal end of the elongate shaft for making a fluid connection with the at least one lumen. 
     The device can include a fluid reservoir and a flush dome in fluid communication with the lumen of the needle, wherein actuation of the flush dome is effective to pump fluid from the reservoir through the lumen of the needle. 
     In some embodiments, a catheter includes an elongate body having one or more fluid lumens formed therein; and a fluid port formed in the catheter, the fluid port being defined by a helical slit formed in a wall of the catheter. 
     The catheter can include an atraumatic distal tip defined by a substantially spherical bulb. The catheter can include a second, distal-facing fluid port. The helical slit can be formed in a sidewall of a reduced-diameter portion of the catheter. The catheter can include a tapered transition between a main body of the catheter and a reduced-diameter portion of the catheter. 
     In some embodiments, a patient-specific infusion method includes determining a total CSF volume of a patient; aspirating a volume of CSF from the patient based on the determined total CSF volume of the patient; and infusing a drug into an intrathecal space of the patient. 
     The method can include, after infusing the drug, infusing the aspirated CSF of the patient to push the drug in a desired direction within the intrathecal space. The total CSF volume can be determined from a pre-operative image of the patient&#39;s central nervous system. The aspirated volume of CSF can be in the range of about 1% to about 20% of the total CSF volume of the patient. The drug can be infused while the volume of CSF is aspirated. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic view of a drug delivery system; 
         FIG. 2  is a perspective view of a catheter that can be used with the system of  FIG. 1 ; 
         FIG. 3A  is a perspective view of a tip of the catheter of  FIG. 2 ; 
         FIG. 3B  is a sectional view of the tip of the catheter of  FIG. 2 ; 
         FIG. 3C  is a series of design views of the tip of the catheter of  FIG. 2 ; 
         FIG. 4  is a sectional view of a body of the catheter of  FIG. 2 ; 
         FIG. 5  is a perspective view of a hub of the catheter of  FIG. 2 , with a portion of the hub shown as transparent; 
         FIG. 6A  is a sectional view of the hub of  FIG. 5 , shown with integrated connectors; 
         FIG. 6B  is an end view of the hub of  FIG. 5 , shown with integrated connectors; 
         FIG. 7A  is a plan view of a first bend profile of a guidewire of the catheter of  FIG. 2 ; 
         FIG. 7B  is a plan view of a second bend profile of a guidewire of the catheter of  FIG. 2 ; 
         FIG. 7C  is a plan view of a third bend profile of a guidewire of the catheter of  FIG. 2 ; 
         FIG. 8A  is a perspective, partially-transparent view of a tip that can be used with the catheter of  FIG. 2 ; 
         FIG. 8B  is a profile, partially-transparent view of the tip of  FIG. 8A ; 
         FIG. 9  is a perspective, partially-transparent view of the body of the catheter of  FIG. 2 , shown with a side exit port; 
         FIG. 10  is a perspective and end view of a tip that can be used with the catheter of  FIG. 2 ; 
         FIG. 11  is a perspective and end view of a tip that can be used with the catheter of  FIG. 2 ; 
         FIG. 12  is a perspective view with a detail, partially-transparent inset of a catheter that can be used with the system of  FIG. 1 ; 
         FIG. 13  is a perspective view with a detail, partially-transparent inset of a catheter that can be used with the system of  FIG. 1 ; 
         FIG. 14  is a perspective view with a detail, partially-transparent inset of a catheter that can be used with the system of  FIG. 1 ; 
         FIG. 15  is a perspective view with a detail, partially-transparent inset of a catheter that can be used with the system of  FIG. 1 ; 
         FIG. 16  is a schematic view of a focused ultrasound system that can be used with the system of  FIG. 1 ; 
         FIG. 17  is a schematic hardware diagram of a controller of the system of  FIG. 1 ; 
         FIG. 18  is a functional block diagram of the controller of  FIG. 17 ; 
         FIG. 19  is a screen capture of a graphical user interface that can be implemented by the controller of  FIG. 17 ; 
         FIG. 20A  is a perspective view of a catheter of the system of  FIG. 1  implanted in a patient and shown with an infusion port; 
         FIG. 20B  is a perspective schematic view of the catheter and patient of  FIG. 20A ; 
         FIG. 20C  is a perspective view of the catheter and patient of  FIG. 20A , shown with an infusion port, an injector, and a controller; 
         FIG. 20D  is a perspective view of a distal fluid port of the catheter of  FIG. 20A ; 
         FIG. 20E  is a perspective view of a middle or proximal fluid port of the catheter of  FIG. 20A ; 
         FIG. 21A  is a diagram illustrating the controller of the system of  FIG. 1  coordinating control of a pump with a sensed physiological parameter; 
         FIG. 21B  is a diagram illustrating use of the system of  FIG. 1  to synchronize delivery of a drug with an ascending wave of the patient&#39;s natural CSF pulsation; 
         FIG. 21C  is a diagram illustrating use of the system of  FIG. 1  to synchronize delivery of a drug with a descending wave of the patient&#39;s natural CSF pulsation; 
         FIG. 22  is a schematic diagram of a drug delivery system with a smart lumbar puncture needle; 
         FIG. 23  is a schematic diagram of a drug delivery system with manual pumps; 
         FIG. 24A  is a schematic view of a drug delivery system; 
         FIG. 24B  is a perspective view of a needle, hub, and catheter of the system of  FIG. 24A ; 
         FIG. 24C  is a perspective view of a needle, hub, and catheter of the system of  FIG. 24A , shown with the catheter outside of the needle; 
         FIG. 24D  is a perspective view of a needle, hub, and catheter of the system of  FIG. 24A , shown with the catheter inserted through the needle; 
         FIG. 24E  is a perspective view of a catheter of the system of  FIG. 24A  protruding from a needle of the system of  FIG. 24A ; 
         FIG. 24F  is a perspective view of a catheter of the system of  FIG. 24A  protruding from a needle of the system of  FIG. 24A ; 
         FIG. 24G  is a perspective view of a catheter of the system of  FIG. 24A  protruding from a needle of the system of  FIG. 24A ; 
         FIG. 25A  is a side view of a catheter tip having a helical fluid port; 
         FIG. 25B  is a schematic representation of the geometry of the helical port of  FIG. 25A ; 
         FIG. 25C  is a perspective view of the catheter tip of  FIG. 25A ; 
         FIG. 25D  is another perspective view of the catheter tip of  FIG. 25A ; 
         FIG. 25E  is a photograph of an exemplary distribution pattern achieved using the catheter tip of  FIG. 25A ; 
         FIG. 26  is a schematic diagram of an exemplary method of using the system of  FIG. 24A  with a patient; 
         FIG. 27  is a schematic diagram of an exemplary method of patient-specific infusion; 
         FIG. 28A  is a schematic view of a drug delivery system; 
         FIG. 28B  is a side view of a tip of a needle of the system of  FIG. 28A ; 
         FIG. 29  is a sectional side view of a tip of another needle that can be used with the system of  FIG. 28A ; 
         FIG. 30A  is a schematic view of a tip of another needle that can be used with the system of  FIG. 28A ; 
         FIG. 30B  is a schematic view of the needle tip of  FIG. 30A  with an inflatable member deployed therefrom; and 
         FIG. 30C  is a schematic view of the needle tip of  FIG. 30A  with a fluid being infused through the inflatable member. 
     
    
    
     DETAILED DESCRIPTION 
     Drug delivery systems and methods are disclosed herein. In some embodiments, a drug delivery system can be configured to deliver a drug to a patient in coordination with a physiological parameter of the patient (e.g., the patient&#39;s natural cerebrospinal fluid (CSF) pulsation or the patient&#39;s heart or respiration rate). In some embodiments, a drug delivery system can be configured to use a combination of infusion and aspiration to control delivery of a drug to a patient. Catheters, controllers, and other components for use in the above systems are also disclosed, as are various methods of using such systems. 
     Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the methods, systems, and devices disclosed herein. One or more examples of these embodiments are illustrated in the accompanying drawings. Those skilled in the art will understand that the methods, systems, and devices specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present disclosure. 
     In some embodiments, systems and methods are provided in which a drug is injected or otherwise delivered to the central nervous system of a patient in coordination with the natural CSF flow. For example, the drug can be injected in a plurality of stages synchronized in phase and/or frequency with the natural CSF pulse. The systems and methods herein can allow for a drug to be delivered more efficiently to a patient than in the case of traditional techniques. For example, a smaller quantity of the drug can be delivered and still reach the target destination, thereby reducing cost and/or possible side effects of delivering a large quantity of the drug. 
     The systems and methods disclosed herein can be used in applications where the intended delivery target is not accessible or not accessible in a minimally-invasive manner, but instead more readily-accessible and safer injection sites which are in direct fluid communication with the intended delivery site exist. For example, a drug can be delivered to the intrathecal space of a patient via an injection site in the patient&#39;s spine (e.g., a lumbar region, a thoracic region, a cervical region, and so forth) and can be transported via the intrathecal space to a target location that is cranial to the injection site (e.g., the brain or a more-cranial region of the spine). In other embodiments, the drug can be transported to a location that is caudal to the injection site. 
     The systems and methods disclosed herein can include fully programmable customized injection and/or aspiration profiles which can be synchronized by real-time monitoring of physiological parameters of the patient, such as heart rate, CSF pressure, CSF pulsation rate, respiration rate, lung capacity, chest expansion and contraction, intrathoracic pressure, intraabdominal pressure, and the like. This can allow the end user to fine-tune injection/aspiration doses per cycle, time length and profile of each microinjection, relative timing (or phase) of microinjections, and other parameters. The systems and methods disclosed herein can include real-time inline pressure sensing for estimating drug delivery efficiency and ensuring patient safety. 
     The systems and methods disclosed herein can include custom built catheters with various lumen quantities, lumen sizes, port placement locations, and other properties. The catheters can be directionality-optimized for efficient mixing and/or such that they are adapted for a particular anatomy. 
       FIG. 1  is a schematic diagram of an exemplary drug delivery system  100 . As shown, the system  100  can include a catheter  102 , a controller  104 , a pump or actuator  106 , and one or more sensors  108 . The pump  106  can be configured to pump a drug or a drug-containing fluid through the catheter  102  and into a patient  110  (e.g., into an intrathecal space of the patient). The pump  106  can also be configured to aspirate fluid from the patient. The pump  106  can be controlled by the controller  104  to synchronize or otherwise coordinate delivery of the drug and/or aspiration of fluid with a physiological parameter of the patient, which can be measured by the sensor  108 . Exemplary physiological parameters can include heart rate, CSF pressure, CSF pulsation rate, respiration rate, lung capacity, chest expansion and contraction, intrathoracic pressure, intraabdominal pressure, and the like. 
     An exemplary catheter  102  which can be used with the system  100  is shown in  FIG. 2 . The catheter  102  can include a tip portion  112 , a body  114 , and a hub  116 . A first portion  114   d  of the body  114  can extend between the tip  112  and the distal end of the hub  116 . A second portion  114   p  of the body  114  can extend proximally from the hub  116  to one or more connectors  118  or other features for coupling the catheter  102  to the system  100 , e.g., for attaching the catheter to the pump  106 . The catheter  102  can have an overall length of about 1 meter. 
     The tip  112  of the catheter  102  is shown in more detail in  FIGS. 3A-3C . The tip  112  can include a generally cylindrical body with a conical, bulleted, or tapered tip. The tip  112  can provide an atraumatic lead-in surface to facilitate tunneling the catheter  102  through tissue or through a lumen of the patient, such as the intrathecal space. The tip  112  can include one or more fluid lumens formed therein, and a corresponding one or more fluid ports through which fluid can be communicated from the fluid lumen to an exterior of the catheter and vice-versa. In the illustrated embodiment, the tip  112  includes a first fluid lumen  120 A with a first fluid port  122 A and a second fluid lumen  120 B with a second fluid port  122 B, though it will be appreciated that the tip can include any number of fluid lumens (e.g., zero, one, two, three, four, five, more than five, etc.) and any number of fluid ports (e.g., zero, one, two, three, four, five, more than five, etc.). The fluid ports  122 A,  122 B can be aimed in a substantially distal direction and can be offset from the central longitudinal axis of the tip  112 , as shown. In other embodiments, the fluid ports  122 A,  122 B can be aimed laterally, e.g., in a direction substantially perpendicular to the central longitudinal axis of the tip  112 . Having the fluid ports slightly offset from center or aimed laterally can advantageously reduce the risk of the ports becoming occluded during insertion or use of the catheter  102 . 
     The catheter  102  can include a steering mechanism to facilitate remote positioning of the catheter within the patient. For example, the catheter  102  can be configured to receive a guidewire  124  therethrough to allow the catheter to be inserted over the guidewire or to be steered by the guidewire. In the illustrated embodiment, the tip  112  includes a guidewire lumen  126 . The guidewire lumen  126  can be a closed, blind hole as shown, or can be open to an exterior of the tip  112 . Alternatively, or in addition, the catheter  102  can include one or more steering wires (not shown) that terminate at the tip  112 . The wires can extend proximally from the tip  112  to a proximal end of the catheter  102 , where they can be selectively tensioned to steer the tip of the catheter within the patient. For example, the catheter  102  can include first and second steering wires that extend longitudinally therethrough and which are anchored to the tip  112  at diametrically-opposed locations about the outer periphery of the tip. The steering wires can extend through respective sleeves or tubes in the body  114  of the catheter  102  to the proximal end of the catheter where tension can be selectively applied thereto to steer the tip  112  of the catheter. 
     The tip  112  can be formed from various materials, including biocompatible materials, stainless steel, titanium, ceramics, polymers, and the like. The tip  112  can be radiopaque or can include one or more radiopaque markers to facilitate visualization under fluoroscopy or other imaging techniques. 
     The tip  112  can have an outside diameter of about 3 French to about 5 French. The tip  112  can have an outside diameter of about 1 mm to about 3 mm. 
       FIG. 4  is a cross-sectional view of the distal portion  114   d  of the catheter body  114 . As shown, the body  114  can include an outer sheath  128  that defines an interior channel  130 . One or more fluid tubes  132 A,  132 B can be disposed within the interior channel, each fluid tube defining a respective fluid lumen  134 A,  134 B. The interior channel  130  can also contain a guidewire  124  or one or more steering wires (not shown). In the illustrated embodiment, the distal body portion  114   d  includes a first fluid tube  132 A having a lumen  134 A in fluid communication with the first fluid lumen  120 A of the tip  112 , a second fluid tube  132 B having a lumen  134 B in fluid communication with the second fluid lumen  120 B of the tip, and a guidewire  124 . 
     The sheath  128  can have various cross-sectional profiles. For example, the sheath  128  can have a circular transverse cross-section that defines a single interior channel  130  as shown. By way of further example, the sheath  128  can have multiple interior channels. Each of the fluid tubes  132 A,  132 B can be disposed within its own independent channel of the sheath  128 , or the sheath itself can define the fluid tubes. The guidewire  124  can be disposed in its own independent channel of the sheath  128  and the fluid tubes  132 A,  132 B can be disposed in a separate channel of the sheath. The guidewire channel can have a circular cross-section and the fluid tube channel can have a crescent or D-shaped cross-section. 
     The fluid tubes  132 A,  132 B can be formed from any of a variety of materials, including fused silica, polyurethane, etc. Use of fused silica can be advantageous when using the system  100  to deliver viruses, as viruses may be less prone to sticking to fused silica fluid tubes. In some embodiments, fluid tubes used for drug delivery can be formed from fused silica and fluid tubes not used for drug delivery (e.g., buffer delivery tubes or aspiration tubes) can be formed from a material other than fused silica, such as polyurethane. The fluid tubes  132 A,  132 B can be coated with a shrink tubing or an outer sheath to provide stress and strain relief for the fluid tubes. The sheath  128  can be formed from any of a variety of materials, including polyurethane. While use of the fluid tubes  132 A,  132 B to communicate fluid is generally described herein, the fluid tubes can also be used for other purposes, such as inserting a biopsy probe or other instrument, or inserting a sensor  108 . 
     The fluid tubes  132 A,  132 B can have an inside diameter of about 0.005 inches to about 0.050 inches. The fluid tubes  132 A,  132 B can have an inside diameter of about 0.010 inches to about 0.020 inches. The body  114  can have an outside diameter of about 3 French to about 5 French. The body  114  can have an outside diameter of about 1 mm to about 3 mm. 
     An exemplary hub  116  is shown in  FIG. 5 . The hub  116  can include respective channels for receiving the first fluid tube  132 A, the second fluid tube  132 B, and the guidewire  124 . Each channel can include proximal and distal openings. The channels can merge within the body of the hub  116  such that they each share a common distal opening. The sheath  128  of the distal body portion  114   d  can be received through the distal opening of the hub  116  and into the guidewire channel of the hub. The fluid tubes  132 A,  132 B can penetrate the sidewall of the sheath  128  within the body of the hub  116 . The hub  116  can thus form a seal between the sheath  128  and the fluid tubes  132 A,  132 B, support the fluid tubes and the guidewire  124 , and guide these components into the inner channel(s)  130  of the sheath of the distal body portion  114   d.    
     The hub  116  can be a “pass-through” type hub in which the first and second fluid tubes  132 A,  132 B extend completely through the hub uninterrupted as shown in  FIG. 5 . Alternatively, as shown in  FIGS. 6A-6B , the first and second fluid tubes  132 A,  132 B can terminate within the hub at respective connector ports  136 A,  136 B. The connector ports  136 A,  136 B can allow selective coupling and decoupling of the proximal body portion  114   p  (e.g., proximal extension tubes) to the first and second fluid tubes  132 A,  132 B. The guidewire  124  can continue to extend completely through the hub  116  uninterrupted, or it too can terminate within the hub at a connector where a proximal guide wire extension can be selectively coupled thereto. Any of a variety of connector types can be used to couple the fluid tubes to the proximal extension tubes, including zero-dead-volume micro-connectors or fittings available from Valco Instruments Co. Inc. of Houston, Tex. 
     The proximal body portion  114   p  can include a sheath similar to that of the distal body portion  114   d , or can be formed by the fluid tubes  132 A,  132 B extending proximally from the hub  116 , or from one or more extension tubes coupled to the fluid tubes  132 A,  132 B at the hub  116 . The proximal end of the catheter  102  can include one or more connectors  118  for making a fluid connection with the fluid tubes  132 A,  132 B of the catheter. For example, as shown in  FIG. 2 , the fluid tubes  132 A,  132 B (or proximal extension tubes as the case may be) can include a connector  118  at a proximal end thereof. Any of a variety of connector types can be used, including zero-dead-volume micro-connectors or fittings available from Valco Instruments Co. Inc. of Houston, Tex. 
     The guidewire  124  can be disposed within the catheter  102  and can be used to guide, steer, or otherwise control insertion of the catheter into the patient. 
     The guidewire  124  can be cylindrical and can have a substantially-straight profile. The guidewire  124  can extend completely through the catheter  102 , or can terminate in a blind bore  126  formed in the tip  112  of the catheter. In use, the guidewire  124  can be inserted into the patient first and guided to a target site, and the catheter  102  can then be inserted over the guidewire to position a portion of the catheter at the target site. In other embodiments, the catheter  102  can be inserted before or simultaneously with the guidewire  124 , and the guidewire can be used to steer or guide the catheter. 
     For example, as shown in  FIGS. 7A-7C , the guidewire  124  can have a resting configuration that deviates from a straight line at or near a distal end of the guidewire. In FIG.  7 A, the guidewire  124  has a straight distal portion  124   d  and a straight proximal portion  124   p  joined by a curved elbow such that a central longitudinal axis of the distal portion extends at an oblique angle with respect to a central longitudinal axis of the proximal portion. In  FIG. 7B , the guidewire  124  has a curved distal portion  124   d  joined to a straight proximal portion  124   p  such that a central longitudinal axis of the distal portion extends at an oblique angle with respect to a central longitudinal axis of the proximal portion. In  FIG. 7C , the guidewire  124  has a straight distal portion  124   d  and a straight proximal portion  124   p  that meet at an angled bend such that a central longitudinal axis of the distal portion extends at an oblique angle with respect to a central longitudinal axis of the proximal portion. 
     In use, the guidewire  124  can be used to navigate the catheter  102  through the patient by twisting the proximal end of the guidewire to turn the bent distal portion and thereby steer or aim the catheter. While a single guidewire  124  is shown, it will be appreciated that the catheter  102  can include any number of guidewires and/or guidewire lumens. The guidewire  124  can be formed from any of a variety of materials, including shape-memory metals such as Nitinol. 
     Any of the catheters disclosed herein can be steerable. For example, a steering mechanism can be provided to allow the distal end of the catheter  102  to be guided during insertion or at another desired time. In some embodiments, the catheter  102  can include one or more steering wires having a first end coupled to the distal tip  112  of the catheter and having a second end at the proximal end of the catheter through which tension can be selectively applied to the steering wires to direct or steer the tip of the catheter in a desired direction. The steering wires can be embedded in the sidewalls of the catheter  102  or can extend through a lumen of the catheter. 
     In some embodiments, the catheter  102  can include a coaxial steering catheter (not shown) extending therethrough. A distal end of the steering catheter can be curved or biased towards a curved shape such that, when the steering catheter is deployed distally from the tip of the primary catheter  102 , the primary catheter can be steered or guided along the curve of the steering catheter. The steering catheter can then be retracted back into the primary catheter  102  to discontinue the curved guidance. The steering catheter can be formed from or can include shape memory or resilient materials such that the steering catheter is deformable between a substantially straight line configuration when retracted into the primary catheter  102  and a flexed or curved configuration when deployed from the primary catheter. The steering catheter can be longitudinally translatable relative to the primary catheter  102  to allow for deployment and retraction. 
     Any of the catheters disclosed herein can include a camera or imaging device, which can be integral with the catheter or can be inserted through a working channel of the catheter. Any of the catheters disclosed herein can include markings visible under fluoroscopy, CT, MRI, or other imaging techniques to allow the catheter to be visualized in images captured using such techniques. 
     The catheter  102  can be configured to withstand high internal pressures. The catheter  102  can be configured to withstand a pressure of at least about 100 psi, at least about 200 psi, and/or at least about 500 psi. 
     It will be appreciated that a number of variations on the above-described catheter  102  are possible. For example, one or more of the fluid ports can be aimed to the side such that they exit a lateral sidewall of the catheter.  FIGS. 8A-8B  illustrate an exemplary catheter tip having side-facing ports. As shown, the tip  112  includes a first fluid lumen  120 A that extends to a distal-facing port  122 A. The distal-facing port  122 A can be formed in an angled or slash-cut distal face of the tip  112 . The tip  112  also includes a second fluid lumen  120 B that extends to a side-facing port  122 B. The tip  112  can also include a guidewire lumen for receiving the distal end of a guide wire  124 . In some embodiments, the central channel  130  of the sheath  128  can act as a fluid lumen, e.g., for delivering a buffer or for delivering a drug. The tip  112  can include a side-facing port  122 C in fluid communication with the central channel  130  of the sheath  128 . 
     The catheter  102  can include one or more fluid ports formed proximal to the tip portion  112  of the catheter, e.g., formed in the body  114  of the catheter.  FIG. 9  illustrates an exemplary catheter body  114  having a side-facing port  122 B. As shown, one or more of the fluid tubes  132 A,  132 B extending through the sheath  128  of the body  114  can terminate within the body or can otherwise have a fluid port disposed in the body. The sheath  128  can have a slit or opening  122 B aligned with the port of the fluid tube  132 B, such that fluid exiting the fluid tube can flow through the opening in the sheath or such that fluid can flow through the sheath and into the port of the fluid tube. The catheter  102  can include one or more plugs  138  disposed within the channel  130  of the sheath  128  to prevent fluid exiting or entering the fluid tube  132 B from flowing proximally and/or distally within the sheath, instead guiding the fluid out of the sheath through the opening or slit  122 B formed therein, or guiding incoming fluid into the fluid port of the tube. The plugs  138  can be formed from a rigid material, from an adhesive, silicone, or various other materials. 
     The fluid lumens of the catheter can have various internal geometries to control or direct the delivery pattern of fluid delivered therethrough.  FIG. 10  illustrates an exemplary catheter tip  112  in which one of the fluid lumens  120 A has a thread formed on an interior surface thereof to define a helical or “corkscrew” shape. The helical shape of the fluid lumen  120 A can promote turbulent flow of fluid therefrom encouraging dispersion or even distribution of the fluid. It will be appreciated that more than one of the fluid lumens can have a helical tip.  FIG. 11  illustrates an exemplary catheter tip  112  in which one of the fluid lumens  120 A tapers or narrows towards the distal end to create a nozzle. This nozzle can create a jet-stream effect, increasing the velocity of the infusate as it is delivered. It will be appreciated that more than one of the fluid lumens can have a nozzle tip. As also shown in  FIGS. 10-11 , one or more of the fluid lumens can have a simple cylindrical tip. 
     As noted above, the catheter  102  can include any number of lumens extending therethrough. In some embodiments, a dual-lumen catheter can be used. The dual lumen catheter can include an infusion lumen and a pressure sensor lumen, an infusion lumen and an aspiration lumen, two infusion lumens, etc. In other embodiments, a tri-lumen catheter can be used. The tri-lumen catheter can include an infusion lumen, an aspiration lumen, and a pressure sensor lumen, two infusion lumens and an aspiration lumen, three infusion lumens, etc.  FIG. 10  illustrates an exemplary tri-lumen catheter having an infusion lumen  120 A, an aspiration lumen  120 B, and a pressure sensor lumen  120 C.  FIG. 11  illustrates an exemplary dual-lumen catheter an infusion lumen  120 A and an aspiration lumen  120 B. 
     The catheter can include a valve system to control the direction of fluid flow therethrough. For example, a valve system can include one-way valves on each lumen to prevent infusion into an aspiration lumen and vice versa. The valve system can facilitate use of a single syringe or other pump to infuse and withdraw fluid, or can facilitate infusion and aspiration through a single lumen. 
     As discussed further below, the sensor  108  can be mounted to the catheter  102 , formed integrally with the catheter, threaded through a lumen of the catheter, etc. For example, the catheter  102  can include a sensor  108  embedded in the tip portion  112  of the catheter, or can include a sensor threaded through a dedicated sensor lumen of the catheter. 
     One or more of the fluid lumens through the catheter can have fluid ports that are longitudinally offset from fluid ports of other lumens of the catheter. For example, as shown in  FIG. 12 , the catheter  102  can include a first fluid lumen  120 A that extends to a fluid port  122 A formed at the terminal distal end of the catheter. The catheter  102  can also include a second fluid lumen  120 B that extends to fluid ports  122 B which are spaced a distance D apart from the distal end of the catheter in a proximal direction. As shown, the second fluid lumen  120 B can include one or more side-facing ports  122 B. In other embodiments, the second fluid lumen  120 B can include a distal facing port. In use, one of the fluid lumens  120 A,  120 B can be used to deliver a drug or other fluid and the other fluid lumen can be used to aspirate fluid from the patient. The catheter  102  can thus be used to create a “push-pull” effect at a target site, in which a drug is infused at the distal end of the catheter via the first fluid lumen  120 A and then drawn back toward the proximal end of the catheter by the flow of fluid being aspirated through the second fluid lumen  120 B. The opposite arrangement can also be used, in which the drug is infused through the proximal port(s) and aspirated through the distal port(s). A proximal end of the catheter  102  can have first and second connectors  118 A,  118 B corresponding respectively to the first and second fluid lumens  120 A,  120 B. The offset fluid ports  122 A,  122 B can be used to coordinate delivery with a physiological parameter of the patient, such as natural CSF flow. An external peristaltic pump or other device can be used to drive the infusion and/or aspiration. As shown, the outer sheath  128  of the body  114  can taper inward to the first lumen  120 A after the termination of the second lumen  120 B. 
     The catheter  102  can include features for controlling delivery of fluid through the catheter. For example, as shown in  FIG. 13 , the catheter  102  can include an internal auger  140 . The auger  140  can have an elongate flexible shaft  142  that extends through the catheter  102  to a proximal end of the catheter, where it can be coupled to a motor for driving rotation of the auger. The motor can be part of the controller  104  or can be a separate component. The controller  104  can start and stop rotation of the auger  140 , and/or can control the speed or direction of auger rotation to control delivery of fluid through the fluid lumen  120  in which the auger is disposed. The auger  140  can be disposed in a fluid tube  132  extending through a sheath portion  128  of the catheter  102 . The auger  140  can also be disposed distal to a terminal distal end of a fluid tube  132 , with the auger shaft  142  extending through the fluid tube. The auger  140  can thus be disposed within the sheath  128  of the catheter  102  but distal to a fluid tube  132  of the catheter. The auger  140  can advantageously control fluid delivery through the catheter  102  and generate more turbulent flow of fluid from the catheter. A proximal end of the catheter can have first and second connectors  118 A,  118 B corresponding respectively to the first and second fluid lumens and a third port or connector  118 C through which the auger shaft  142  can extend. The auger  140  can be used to coordinate delivery with a physiological parameter of the patient, such as natural CSF flow. 
     By way of further example, as shown in  FIG. 14 , the catheter  102  can include an internal, reciprocating piston or inner tube  144 . The catheter  102  can include a fixed outer tube  128  and a slidable inner tube  144  disposed coaxially within the outer tube. The inner tube  144  can be configured to translate longitudinally with respect to the outer tube  128 . The inner tube  144  can include a valve  146 , e.g., at a terminal distal end thereof. Exemplary valves include one-way valves, duck-bill valves, spring-biased check valves, and the like. A seal can be formed between the inner tube  144  and the outer tube  128 , e.g., at a proximal end of the catheter  102 . In use, the inner tube  144  can be loaded with a drug-containing fluid. The inner tube  144  can then be pulled proximally with respect to the outer tube  128  to cause the drug-containing fluid to flow through a one-way valve  146  into the distal end of the outer tube. The inner tube  144  can then be pushed distally, closing the one-way valve  146  and expelling the drug-containing fluid out of the distal end of the outer tube  128  and into the patient. The translating tubes  128 ,  144  can allow a fixed or predetermined volume of drug-containing infusate to be delivered with each reciprocation of the inner tube  144 . The proximal ends of the outer and inner tubes  128 ,  144  can include connectors  118 A,  118 B, e.g., for supplying fluid to the outer and inner tubes. The reciprocating inner tube  144  can be used to coordinate delivery with a physiological parameter of the patient, such as natural CSF flow. 
     As another example, as shown in  FIG. 15 , the catheter  102  can include a transducer  148 , such as a piezoelectric transducer, to help control delivery of a drug through the catheter. The transducer  148  can be formed on a flex circuit or other substrate disposed adjacent to a fluid port  122  of the catheter  102 . The transducer  148  can include an electrically-conductive lead or wire  150  that extends proximally therefrom through the catheter  102  to the controller  104 . In use, an electric potential can be applied to the transducer  148  to induce vibration or other movement of the transducer. This movement can control distribution of the drug from the catheter  102 . For example, the transducer  148  can control the direction in which the infusate flows as it exits the catheter  102 , can control the opening or closing of a fluid port  122  of the catheter, and/or can control the volume of infusate that exits the catheter. A proximal end of the catheter  102  can have first and second connectors  118 A,  118 B corresponding respectively to first and second fluid lumens and a third port or connector  118 C through which the electrical conductor  150  of the transducer  148  can extend. The transducer  148  can be used to coordinate delivery with a physiological parameter of the patient, such as natural CSF flow. 
     The system  100  can include one or more transducers for delivering focused ultrasound to the patient. As shown in  FIG. 16 , a focused ultrasound system  152  can aim ultrasonic waves toward a location at which drug-containing infusate  154  exits the catheter  102 . The focused ultrasound can enhance dispersion of the drug, and/or control the direction and degree to which the drug disperses. Focused ultrasound can be used to coordinate delivery with a physiological parameter of the patient, such as natural CSF flow. Focused ultrasound can also be used to enhance or direct drug distribution without pulsatile delivery. 
       FIG. 17  illustrates a block diagram of the physical components of an exemplary embodiment of the controller  104 . Although an exemplary controller  104  is depicted and described herein, it will be appreciated that this is for sake of generality and convenience. In other embodiments, the controller  104  may differ in architecture and operation from that shown and described here. The controller  104  can be a tablet computer, mobile device, smart phone, laptop computer, desktop computer, cloud-based computer, server computer, and so forth. One or more portions of the controller  104  can be implanted in the patient. Delivery control software can execute on the controller  104 . The software can execute on a local hardware component (e.g., a tablet computer, smart phone, laptop computer, or the like) or can execute remotely (e.g., on a server or cloud-connected computing device in communications coupling with the controller). 
     The illustrated controller  104  includes a processor  156  which controls the operation of the controller  104 , for example by executing embedded software, operating systems, device drivers, application programs, and so forth. The processor  156  can include any type of microprocessor or central processing unit (CPU), including programmable general-purpose or special-purpose processors and/or any of a variety of proprietary or commercially-available single or multi-processor systems. As used herein, the term processor can refer to microprocessors, microcontrollers, ASICs, FPGAs, PICs, processors that read and interpret program instructions from internal or external memory or registers, and so forth. The controller  104  also includes a memory  158 , which provides temporary or permanent storage for code to be executed by the processor  156  or for data that is processed by the processor. The memory  158  can include read-only memory (ROM), flash memory, one or more varieties of random access memory (RAM), and/or a combination of memory technologies. The various components of the controller  104  can be interconnected via any one or more separate traces, physical busses, communication lines, etc. 
     The controller  104  can also include an interface  160 , such as a communication interface or an I/O interface. A communication interface can enable the controller  104  to communicate with remote devices (e.g., other controllers or computer systems) over a network or communications bus (e.g., a universal serial bus). An I/O interface can facilitate communication between one or more input devices, one or more output devices, and the various other components of the controller  104 . Exemplary input devices include touch screens, mechanical buttons, keyboards, and pointing devices. The controller  104  can also include a storage device  162 , which can include any conventional medium for storing data in a non-volatile and/or non-transient manner. The storage device  162  can thus hold data and/or instructions in a persistent state (i.e., the value is retained despite interruption of power to the controller  104 ). The storage device  162  can include one or more hard disk drives, flash drives, USB drives, optical drives, various media disks or cards, and/or any combination thereof and can be directly connected to the other components of the controller  104  or remotely connected thereto, such as through the communication interface. The controller  104  can also include a display  164 , and can generate images to be displayed thereon. In some embodiments, the display  164  can be a vacuum fluorescent display (VFD), an organic light-emitting diode (OLED) display, or a liquid crystal display (LCD). The controller  104  can also include a power supply  166  and appropriate regulating and conditioning circuitry. Exemplary power supplies include batteries, such as polymer lithium ion batteries, or adapters for coupling the controller  104  to a DC or AC power source (e.g., a USB adapter or a wall adapter). 
     The various functions performed by the controller  104  can be logically described as being performed by one or more modules. It will be appreciated that such modules can be implemented in hardware, software, or a combination thereof. It will further be appreciated that, when implemented in software, modules can be part of a single program or one or more separate programs, and can be implemented in a variety of contexts (e.g., as part of an embedded software package, an operating system, a device driver, a standalone application, and/or combinations thereof). In addition, software embodying one or more modules can be stored as an executable program on one or more non-transitory computer-readable storage mediums. Functions disclosed herein as being performed by a particular module can also be performed by any other module or combination of modules, and the controller can include fewer or more modules than what is shown and described herein.  FIG. 18  is a schematic diagram of the modules of one exemplary embodiment of the controller  104 . 
     As shown in  FIG. 18 , the controller  104  can include a sensor input module  168  configured to receive information from the sensor(s)  108 . The sensor input module  168  can read and interpret output signals supplied from the sensors  108  to the processor  156 , e.g., via a general purpose input/output pin of the processor. The sensor input module  168  can optionally perform various processing on the sensor signals, such as frequency detection, phase detection, debouncing, analog-to-digital conversion, filtering, and so forth. 
     The controller  104  can also include a delivery control module  170  configured to control the pump or actuator  106  to infuse or aspirate fluid from the patient and/or to control the catheter  102  (e.g., an auger, piston, transducer, ultrasound system, etc.). For example, when an “infuse” instruction is issued, the delivery control module  170  can cause power to be supplied to the pump  106  to begin pumping infusate through the catheter  102 , or cause an electronically-actuated valve to open such that infusate stored under pressure is placed in fluid communication with the catheter and flows therethrough. In some embodiments, the delivery control module  170  can be configured to cut off power to the pump  106  or to close a valve when a pressure sensor indicates that the pressure in the system has reached a predetermined threshold amount. When an “aspirate” instruction is issued, the delivery control module  170  can cause power to be supplied to the pump  106  to begin pumping fluid out of the catheter  102 . 
     The controller  104  can include a user input module  172  configured to receive one or more user inputs, e.g., as supplied by a user via the interface  160 . Exemplary user inputs can include infusion parameters, patient information, treatment protocols, and so forth, as discussed further below. 
     The controller  104  can also include a display module  174  configured to display various information to the user on the display  164 , such as a graphical or textual user interface, menus, buttons, instructions, and other interface elements. The display module  174  can also be configured to display instructions, warnings, errors, measurements, and calculations. 
       FIG. 19  illustrates an exemplary graphical user interface  176  that can be displayed to the user by the display module  174  and through which a user can supply information to the user input module  172 . The illustrated interface  176  is configured for use with a pump system  106  that includes first and second motors or linear actuators that can be operated to apply a force to respective syringe pumps for delivering infusate to the catheter  102  and for withdrawing or aspirating fluid from the catheter. 
     The user interface  176  can include a motor communication panel  178  for displaying various information associated with the motors. This information can include the connection status of the motors, an IP or other software address of the motors, and a motor communication frequency or update time. The user can interact with the motor communication panel  178  to select or change the motor addresses and the update time. 
     The user interface  176  can include a motor setting panel  180  for adjusting various motor settings and for displaying the current setting to the user. The motor setting panel  180  can include controls for the motor velocity, motor acceleration, distance of syringe movement as a function of motor steps, current motor positions, infusion frequency, infusion amplitude, infusion rate, infusion phase, and so forth. 
     The controller  104  can be configured to control various infusion and/or aspiration parameters to achieve customized delivery. This can allow the delivery to be tailored based on the therapeutic application. Exemplary parameters that can be controlled by the controller  104  include infusion type, infusion rate, infusion volume, time between infusions, oscillatory rate, infusion and withdraw ratio, infusion phase timing, aspiration type, aspiration rate, time between aspirations, aspiration volume, and so forth. 
     The pump or actuator system  106  can be configured to supply a drug or a drug-containing fluid to the catheter  102  and/or to aspirate fluid from the catheter. The system  106  can include one or more pumps. For example, the system  106  can include a plurality of pumps, each being associated with and in fluid communication with a corresponding lumen of the catheter  102 . The pumps can also be associated with and in fluid communication with respective reservoirs for holding a volume of fluid. In some embodiments, the system  106  can include first and second syringe pumps coupled to electronic linear actuators configured to advance or retract the plungers of the syringe pumps in response to control signals received from the controller  104 . In some embodiments, the system  106  can include a peristaltic pump, an auger pump, a gear pump, a piston pump, a bladder pump, etc. One or more portions of the system  106  can be implanted in the patient. The system  106  can include any of a variety of implantable or extracorporeal pumps. In some embodiments, the system  106  can include a fully-implanted, programmable pump and a fully-implanted fluid reservoir containing fluid to be delivered using the system. In some embodiments, the entire system  106  can be implantable, e.g., to facilitate chronic treatment methods. 
     The sensor  108  can be a single sensor or a plurality of sensors. Exemplary sensors include pressure sensors, electrocardiogram sensors, heart rate sensors, temperature sensors, PH sensors, respiration rate sensors, respiration volume sensors, lung capacity sensors, chest expansion and contraction sensors, intrathoracic pressure sensors, intraabdominal pressure sensors, and the like. One or more of the sensors  108  can be implanted in the patient. One or more of the sensors  108  can be mounted on, inserted through, or formed in or on the catheter  102 . The sensors  108  can also be remote from the catheter  102 . In some embodiments, the sensors  108  can include a pressure sensor disposed in or on the catheter  102  for measuring CSF pressure adjacent to the catheter and an ECG sensor for measuring the patient&#39;s heart rate. The sensors  108  can be connected (via wires or via a wireless connection) to the sensor input module  168  of the controller  104 . 
     As noted above, one or more components of the delivery system  100  and, in some embodiments, all components of the delivery system, can be implanted in the patient. Implanting some or all of the delivery system  100  can facilitate chronic or long-term drug delivery (e.g., over a period of days, weeks, months, or years) via non-invasive or outpatient procedures. 
       FIGS. 20A-20B  illustrate the catheter  102  fully-implanted in a patient. As shown, the catheter  102  can be configured for positioning within a patient&#39;s intrathecal space and can extend substantially the entire length of the spinal column or along any portion thereof. The catheter  102  can include one or more fluid lumens. The catheter  102  can also include one or more fluid ports. In some embodiments, the catheter  102  can include a plurality of fluid lumens, with each of the plurality of fluid lumens having its own respective fluid port. In the illustrated embodiment, the catheter  102  includes three fluid lumens and three respective fluid ports  122 P,  122 M, and  122 D. The catheter  102  can also include one or more sensors  108  (e.g., pressure sensors). In the illustrated embodiment, each of the fluid ports  122 P,  122 M,  122 D includes a sensor  108 P,  108 M,  108 D mounted adjacent or in proximity thereto. A proximal end of the catheter  102  can be coupled to a fully implanted, transcutanous, or extracorporeal infusion port  182  through which fluid can be delivered to (or removed from) the various lumens of the catheter and through which one or more sensors  108  on the catheter can be coupled to a controller  104  or other device. A quick-connector system  184  can be used to couple the catheter  102  to the infusion port  182 . The micro-connector  184  can include air and/or bacterial filters and can be a zero-dead-volume connector. The pump  106  and the controller  104  can be mounted together in a chassis or housing  188 , as shown in  FIG. 20C , which can be coupled to an injector  190  configured to mate with the infusion port  182 . The injector  190  can include magnetic alignment features  186  for ensuring that the injector is properly aligned with respect to a subcutaneous infusion port  182 . 
     As shown in  FIG. 20D , the distal or cranial/cervical tip of the catheter  102  can have a modified shape to encourage turbulent flow therethrough (e.g., a helical or corkscrew shaped lumen or fluid port  122 D as described above). Any of a variety of other shapes can be used. The other ports  122 M,  122 P can be similarly configured, can have a simple circular cross-section as shown in  FIG. 20E , or can have any other configuration described herein. 
     The system  100  illustrated in  FIGS. 20A-20E  can be used in acute and/or chronic applications in any of a variety of ways. 
     For example, the catheter  102  can be used to deliver three different drugs (e.g., one drug through each different lumen of the catheter). 
     By way of further example, the catheter  102  can be used for localized delivery of different drugs to different areas of the spine. 
     As yet another example, the catheter  102  can be used to deliver the same drug with substantially instantaneous distribution along the entire spinal column. 
     In another example, one port of the catheter  102  can be used to aspirate while another is used to infuse in order to draw the infused fluid through the spinal canal. In some embodiments, fluid can be infused through a lower-lumbar port  122 P and fluid can be aspirated through a cervical port  122 D to “pull” the infused fluid up the spinal column. 
     In another example, fluid can be infused through a port  122 D disposed in the cervical region of the patient&#39;s spine to propel infused drug into the cranial space. 
     By way of further example, the catheter  102  can be used to substantially contain an infused drug to a given area of the spine. In some embodiments, fluid can be infused through a lower-lumbar port  122 P and fluid can be withdrawn from a mid-lumbar port  122 M to keep the infused drug between the two ports  122 P,  122 M in the lumbar region of the patient&#39;s spine. 
     In an exemplary method, infusions and aspirations via multiple lumens and ports can be staged or combined in a sequence to create and advance a significant bolus at improved, controlled, and convenient rates. The method can include simultaneous aspiration/infusion between deliberately spaced ports. The delivery can be enhanced by a preparation step of removing a safe amount of CSF to be replaced in later procedure steps when advancing the bolus. The method can include a final stage of synchronized pulsatile infusion. The method can allow a large bolus to be formed more quickly, can allow controlled dosing, and/or can allow the bolus to be delivered closer to the brain or other target site. The method can be performed using a catheter that tapers from the proximal end towards the distal end. A tapered catheter profile in which the catheter diameter reduces distal of each port can enable the catheter to be longer, be easier to introduce/navigate, and have device reach significantly closer to the target site. Port designs and locations can be optimized based on dose and other factors. The catheter can be placed such that fluid exiting the ports flows against patient anatomy (e.g., a blind lumen end, lumen sidewall, or lumen constriction) to promote turbulent flow of the infusate upon exiting the catheter. In an initial step, a volume of patient CSF can be aspirated through one or more ports of the catheter. In an exemplary embodiment, about 10% by volume of the patient&#39;s CSF can be aspirated through the catheter and stored in a reservoir. The amount of CSF that is aspirated can be based on a clinically-determined safe level. In a subsequent delivery step, CSF can be aspirated from the patient through a distal fluid port  122 D of the catheter  102  while a drug is simultaneously infused into the patient through a middle port  122 M of the catheter. This can cause a bolus of drug to form between the middle and distal ports  122 M,  122 D. The ports can be located along the length of the catheter to define the bolus size or dose. In an advancement step, the bolus of drug can be advanced within the patient. This can be achieved by infusing previously-aspirated CSF from the reservoir into the patient through a proximal port  122 P of the catheter  102 . This infusion can urge the bolus distally towards the target site and can continue until normal or safe CSF pressure is reached within the patient. While previously-aspirated CSF is used to advance the bolus in the above example, other fluid can be used instead or in addition, such as drug-containing fluid. Before, during, or after advancement of the bolus, infusion of CSF and/or drug-containing fluid can be performed in a pulsatile manner in coordination with one or more physiological parameters of the patient. The above method can also be performed using only a proximal port  122 P and a distal port  122 D. The proximal, middle, and distal ports  122 P,  122 M,  122 D can be spaced along the length of the spinal column as shown in  FIG. 20A , or can all be contained in a discrete region of the spine (e.g., the cervical spine, the thoracic spine, the lumbar spine, etc.). 
     The systems disclosed herein can be used in any of a variety of drug delivery methods. 
     In an exemplary method, the infusion pump  106  can be configured to pump a drug or a drug-containing fluid through the catheter  102  and into a patient (e.g., into an intrathecal space of the patient). The catheter  102  can be inserted into the patient at any of a variety of locations. For example, a percutaneous puncture can be formed in the patient using a needle. The puncture can be formed in the lumbar region of the spine, or in any other region of the spine, e.g., the cervical region between C 1  and C 2 . The needle can have a bent distal tip that helps steer the catheter  102  to be parallel to the spinal cord. The catheter  102  can be inserted through the needle and guided through the intrathecal space along the spinal cord. The infusion can be performed in proximity to the percutaneous puncture, or the catheter  102  can be advanced some distance within the patient. In some embodiments, the catheter  102  can be inserted in the lumbar spine and advanced to the cervical spine or to the cisterna magna. Infusion can be performed at any point along the length of the catheter  102 . Fluid can be infused from a distal end of the catheter  102  (e.g., in a cervical region of the spine), the catheter can be withdrawn proximally, and further infusion can be performed at a more caudal location (e.g., in a lumbar region of the spine). 
     The pump  106  can be controlled by the controller  104  to synchronize or otherwise coordinate delivery of the drug with the patient&#39;s natural CSF flow or pulsation, or with other physiological parameters of the patient (e.g., heart rate, respiration rate, lung capacity, chest expansion and contraction, intrathoracic pressure, intraabdominal pressure, etc.). The infusion profile can be tailored to override the natural CSF pulsation to drive the infusate to a target site. Alternatively, or in addition, the infusion profile can be tailored to coordinate with and leverage the natural CSF pulsation to move the infusate towards the target site. 
     Readings from a pressure sensor  108  can be received by the controller  104 , which can perform signal processing on the sensor output to determine various characteristics of the patient&#39;s CSF flow (e.g., phase, rate, magnitude, etc.). The controller  104  can then control the pump  106  based on these measured characteristics to deliver a drug in coordination with the natural CSF flow, optionally synchronizing the delivery in real time. For example, as shown in the upper portion of  FIG. 21A , the controller  104  can convert the measured pulsatile flow of the CSF into a sinusoidal approximation. The controller  104  can then output a pump control signal, as shown in the lower portion of  FIG. 21A , to drive the infusion pump  106  in coordination with the CSF pulsation. 
     In some instances, the pressure sensed by the pressure sensor  108  can be influenced by the infusion through the catheter  102 . Accordingly, it can be desirable to have another way of detecting or estimating CSF flow. Thus, in some embodiments, the system  100  can be operated initially in a “learning” mode in which no infusion takes place and the controller  104  establishes a correlation between CSF pulsation and heart rate (e.g., as detected by an ECG sensor  108  in communications coupling with the controller). In general, CSF pulsation tracks heart rate with a slight delay. Once a correlation is established, the system  100  can be operated in an “infusion” mode in which infusate is delivered through the catheter  102  and the CSF pulsation is detected or estimated based on measured heart rate (instead of or in addition to detecting or estimating the CSF pulsation based on the pressure sensor  108  output). In other words, the system  100  can interpolate or estimate the CSF flow based on the ECG output, without necessarily having to rely on the pressure sensor output. This can allow the pressure sensor to be used for other purposes, such as monitoring the infusion pressure to allow the controller  104  to automatically regulate delivery to a target pressure or pressure range. 
     In one example use of the systems described herein, a drug can be delivered to the intrathecal space via a simple bolus injection (a fast infusion of a volume of fluid) which then just diffuses slowly along the spinal column. 
     In another example, a bolus injection can be performed to deliver the drug and then the system can be used to create a pulsation behind the bolus by changing oscillation rate/pulsation rate to override the natural CSF pulse and make the bolus move more quickly towards a target location (e.g., the brain). The pulsation can be created by repeatedly withdrawing or aspirating a volume of CSF and then pumping that same volume back into the patient to create a pulse. 
     In another example, infusion of the drug itself can be used to create a pulsation effect to urge the drug along the intrathecal space. In this example, a first volume of the drug can be infused (e.g., 0.1 ml) and then a second, smaller volume can be withdrawn (e.g., 0.05 ml). This can be repeated to create a pulse with a net infusion on each cycle. The process can be repeated until the desired dose is delivered. While an infusion-to-withdrawal ratio of 2:1 is discussed above, it will be appreciated that any ratio can be used. In addition, the rate of infusion and withdrawal can be controlled (e.g., by infusing quickly and withdrawing slowly) to create a burst of fluid towards a target location (e.g., the top of the spinal column). 
     In the devices and methods disclosed herein, infusion and/or aspiration can be coordinated with one or more physiological parameters of a patient (e.g., natural CSF flow, heart rate, respiration rate, etc.). 
     The direction of drug distribution at an intrathecal target site can be controlled at least to some degree based on the timing at which the drug is delivered relative to the timing of the CSF flow. For example, infusion that is synchronized with the ascending wave of CSF flow, as shown in  FIG. 21B , can be distributed to a greater degree in the cranial direction whereas infusion that is synchronized with the descending wave of CSF flow, as shown in  FIG. 21C , can be distributed to a greater degree in the caudal direction of the spinal canal. 
     In some embodiments, a dual- or multi-lumen catheter can be used for alternating, repetitive infusion and aspiration, which can further enhance drug distribution. 
     The systems and methods disclosed herein can provide an improved means for delivering a drug to the intrathecal space, as compared with traditional lumbar bolus injections which do not reach the remote portions of the spinal canal or brain efficiently (if at all). 
     While intrathecal delivery is generally described in the examples given above, it will be appreciated that the systems and methods herein can be used in other applications, with appropriate modification of size or other parameters as will be appreciated by those having ordinary skill in the art. For example, the systems and methods disclosed herein can be used for intrarterial or intravenous delivery. Such systems and methods can include infusion and/or aspiration that is coordinated with one or more physiological parameters of a patient (e.g., natural CSF flow, heart rate, respiration rate, etc.). 
     In some embodiments, the drug can be delivered in a non-pulsatile manner and/or without necessarily coordinating the delivery with a physiological parameter of the patient. For example, alternating or otherwise-coordinated aspiration and infusion can be used to deliver the drug to a target site. By way of further example, the drug can be infused and then a buffer can be infused behind the drug to enhance distribution or to move the drug towards a target site. 
     An exemplary method can include inserting at least a portion of a catheter into a patient and delivering a drug to a target region of the patient. At least a portion of the catheter can be disposed in the target region. The drug can be delivered in a pulsatile manner. The drug can be delivered in coordination with a physiological parameter of the patient (e.g., the patient&#39;s natural CSF flow and/or the patient&#39;s heart rate). 
     The target region can be an intrathecal space of the patient. The target region can be a subpial region of the patient (e.g., a subpial region of the spinal cord and/or a subpial region of the brain). The target region can be a cerebellum of the patient. The target region can be a dentate nucleus of the patient. The target region can be a dorsal root ganglion of the patient. The target region can be a motor neuron of the patient. The drug can include an antisense oligonucleotide. The drug can include a stereopure nucleic acid. The drug can include a virus. The drug can include adeno-associated virus (AAV). The drug can include a non-viral gene therapy. The drug can include vexosomes. The drug can include liposomes. The method can include performing gene therapy by delivering the drug (e.g., by delivering a virus such as AAV). The method can include performing gene editing by delivering the drug (e.g., by delivering a virus such as AAV). The method can include performing gene switching by delivering the drug (e.g., by delivering a virus such as AAV). The method can include performing non-viral gene therapy by delivering the drug (e.g., by delivering vexosomes and/or liposomes). 
     In some embodiments, the method can include determining a total CSF volume of the patient and tailoring the delivery based on the total CSF volume. For example, MRI or other imaging techniques, with or without contrast, can be used to assess the overall CSF volume of the patient. The delivery of the drug can then be tailored based on the measured volume. For example, a larger volume of buffer can be used with patients having a greater total CSF volume and a smaller volume of buffer can be used with patients having a lesser total CSF volume. By way of further example, infusion amplitude, infusion velocity, aspiration volume, aspiration amplitude, and other parameters can be varied in accordance with the measured total CSF volume. 
     The infusion volume can range from about 0.05 mL and about 50 mL. The infusion rate can range from about 0.5 mL/min to about 50 mL/min. 
     The following are exemplary drug delivery methods that can be performed using the systems disclosed herein: 
     Example A 
     Alternating Pulsatile infusions of Drug (Pump 1) and Buffer/Saline (Pump 2) 
     Drug Total Volume: 2.2 mL 
     Buffer Total Volume: 4.4 mL 
     Infusion rate for both pumps: 15 mL/min 
     Cycles: 10 cycles at lumbar then 10 cycles at Cisterna magna 
     Time between cycles: 100 milliseconds 
     Infusion description: At lumbar section Pump 1 infuses 0.11 mL at 15 mL/min, a 100 ms pause, Pump 2 infuses 0.22 mL at 15 mL/min, a 100 ms pause (cycle 1). This is repeated for a total of 10 cycles at the lumbar. Catheter is threaded up to the cisterna magna. Pump 1 infuses 0.11 mL at 15 mL/min, a 100 ms pause, Pump 2 infuses 0.22 mL at 15 mL/min, a 100 ms pause (cycle 1). This is repeated for a total of 10 cycles at the cisterna magna. 
     Example B 
     Alternating Pulsatile infusions of Drug (Pump 1) and Buffer/Saline (Pump 2) 
     Drug Total Volume: 3 mL 
     Buffer Total Volume: 20 mL 
     Infusion rate for both pumps: 4 mL/min 
     Cycles: 13 cycles at thoracic region 
     Time between alternating pump 1 to pump 2: 1000 milliseconds 
     Time between cycles (pump 2 to pump 1): 5000 milliseconds 
     Infusion description: At lumbar section Pump 1 infuses 0.231 mL at 4 mL/min, a 1000 ms pause, Pump 2 infuses 2.0 mL at 4 mL/min, a 5000 ms pause (cycle 1). This is repeated for a total of 13 cycles at the thoracic region. 
     Example C 
     Alternating Pulsatile infusions of Drug (Pump 1) and Buffer/Saline (Pump 2) 
     Drug Total Volume: 5 mL 
     Buffer Total Volume: 8 mL 
     Infusion rate for pump 1: 37 mL/min 
     Infusion rate for pump 2: 20 mL/min 
     Cycles: 5 cycles at thoracic region 
     Time between cycles: 10 milliseconds 
     Infusion description: At lumbar section Pump 1 infuses 1 mL at 37 mL/min, a 10 ms pause, Pump 2 infuses 1.6 mL at 30 mL/min, a 100 ms pause (cycle 1). This is repeated for a total of 5 cycles at the thoracic region. 
       FIG. 22  illustrates a drug delivery system  200  that includes a lumbar puncture needle  292 . The needle  292  can include a sensor  294  (e.g., a pressure sensor) mounted adjacent a distal tip of the needle. Accordingly, upon insertion of the needle  292  into the patient  210 , the sensor  294  can measure the pressure or other properties of the patient&#39;s CSF. The needle  292  can also include an integrated or remote display  296  for displaying the output of the sensor  294  to a user. 
     In some embodiments, the display  296  can be mounted along the length of the needle  292 , distal to a proximal Luer or other connector  298  of the needle. The needle body  292  can be a tubular metal shaft with a sharpened or angled tip. Fluid tubing can be coupled to the needle  292 , e.g., via a proximal connector  298 , and to a programmable pump  106 . A controller  104  of the type described above can be programmed to control the pump  106  to deliver fluid through the needle  292 , e.g., in a pulsatile fashion in coordination with a physiological parameter of the patient. The needle  292  can be used to deliver a drug, to deliver a buffer, and/or to aspirate fluid. In some embodiments, a catheter  102  of the type described above can be inserted through the needle  292  and the fluid delivery or aspiration can be performed through the catheter. 
     As shown in  FIG. 23 , a manual pump  206  can be provided instead of or in addition to the programmable pump  106  and controller  104  shown in  FIG. 22 . As shown, a first fluid lumen of the needle  292  (or of a catheter  102  inserted through the needle) can be coupled to a first pump  206 A that includes a first reservoir and a first flush dome. Similarly, a second fluid lumen of the needle  292  (or of a catheter  102  inserted through the needle) can be coupled to a second pump  206 B that includes a second reservoir and a second flush dome. A user can exert manual finger pressure on the first and second flush domes to selectively press fluid contained in the first and second reservoirs into the patient. Accordingly, the user&#39;s manual actuation rate and actuation pressure can dictate the infusion frequency and volume. A user can thus pulse the delivery manually. The flush domes can be configured such that each successive actuation of the dome delivers a fixed and predetermined volume of fluid. For example, each push of the flush dome can be configured to deliver 0.1 ml of fluid. In some embodiments, one of the reservoirs can be filled with a buffer solution and the other reservoir can be filled with a drug-containing solution. 
       FIGS. 24A-24G  illustrate a drug delivery system  300  that can include a needle  302  and a catheter  304  insertable through the needle. The needle  302  can be a lumbar puncture needle. The catheter  304  can be a single lumen catheter or a multi-lumen catheter. For example, a dual-lumen catheter that bifurcates at a proximal portion of the catheter can be used as shown. Fluid tubing  306  can be coupled to the catheter  304 , e.g., via one or more proximal connectors  308 , and to a programmable pump system  310 . The needle  302  or catheter  304  can also be connected directly to the pump system  310 . 
     In some embodiments, the pump system  310  can include first and second pumps configured to infuse and/or aspirate fluid through respective lumens of the catheter  304 . Any of a variety of pumps can be used, including a linear-actuator syringe pump of the type shown in  FIG. 24A . A controller  104  of the type described above can be programmed to control the pump system  310  to deliver fluid through the catheter  304 , e.g., in a pulsatile fashion in coordination with a physiological parameter of the patient. The catheter  304  can be used to deliver a drug, to deliver a buffer or other fluid, and/or to aspirate fluid. In some embodiments, the catheter  304  can be omitted and fluid can be infused through the needle  302  directly and/or aspirated through the needle directly. One or more of the fluid connections can be made with the needle  302  instead of or in addition to the catheter  304 . For example, the fluid tubing through which a drug is to be delivered can be coupled directly to the catheter  304  to deliver the drug through the catheter and fluid tubing through which a buffer, chaser, or other fluid is to be delivered can be coupled directly to the needle  302  to deliver the fluid through the needle. 
     The needle  302  can be defined by a hollow tubular body configured to receive a catheter and/or fluid therethrough. The needle  302  can be a lumbar puncture needle sized and configured for insertion into the intrathecal space through a lumbar insertion point. The needle  302  can have a curved distal tip configured to naturally steer the needle into the intrathecal space as the needle is inserted into the patient in the lumbar region of the spine. An opening can be formed in the distal end of the needle  302  through which an inserted catheter  304  can extend. 
     The proximal end of the needle can be coupled to a fluid hub  312 . As shown in  FIG. 24B , the hub  312  can be a “W” hub. The hub  312  can include a plurality of ports. The hub  312  can include a distal port to which the needle  302  can be attached and placed in fluid communication with the hub. The hub  312  can include one or more proximal ports. The proximal ports can guide a catheter  304  inserted though the hub  312  into the central lumen of the needle  302 . The proximal ports can attach the hub  312  to respective fluid lines and place the hub in fluid communication with said fluid lines. The fluid lines can be used to direct fluid into the hub  312  and through a needle  302  attached thereto. The proximal and distal ports of the hub  312  can be Luer type connectors or zero-dead-volume connectors. As shown in  FIG. 24B , the hub  312  can include a distal port attached to the needle  302  and a proximal port through which a dual-lumen catheter  304  is inserted to guide the catheter through the needle. The dual lumen catheter  304  can split or bifurcate at a location proximal to the hub  312  into first and second fluid lines, e.g., for carrying a drug and a buffer, respectively. The hub  312  can include one or more additional ports through which a fluid can be introduced into, or withdrawn from, the needle  302 . These ports can be used to deliver drug or buffer to the needle  302  or to aspirate fluid from the needle, instead of or in addition to doing so using the catheter  304 . 
     As shown in  FIGS. 24C-24D , the hub  312  can be a “Y” hub. The hub  312  can include a distal port attached to the needle  302  and a proximal port through which a dual-lumen catheter  304  is inserted to guide the catheter through the needle. The dual lumen catheter  304  can split or bifurcate at a location proximal to the hub  312  into first and second fluid lines, e.g., for carrying a drug and a buffer, respectively. The hub  312  can include one or more additional ports through which a fluid can be introduced into, or withdrawn from, the needle  302 . These ports can be used to deliver drug or buffer to the needle  302  or to aspirate fluid from the needle, instead of or in addition to doing so using the catheter  304 . 
     In some embodiments, the hub can be omitted and fluid can be delivered to or aspirated from the needle  302  directly. For example, the needle  302  can be directly attached to the pump system  310  via one or more fluid lines, or a catheter  304  can be directly attached to the pump system via one or more fluid lines and inserted through the needle without a proximal hub. 
     The system  300  can include one or more valves to control or limit fluid flow through the system. For example, the system  300  can include check valves  314  disposed in-line with respective fluid paths from the pump system  310  to the patient to isolate the paths from one another in a single direction or in both directions. In an exemplary arrangement, the system  300  can include first and second independent fluid sections or channels. The first fluid section or channel can include a first pump configured to deliver a first fluid through a first fluid tube and through a first fluid lumen of the catheter  304 . The second fluid section or channel can include a second pump configured to deliver a second fluid through a second fluid tube and through a second fluid lumen of the catheter  304 . A first valve, e.g., a check valve, can be disposed in the catheter, in the first fluid tube, or in the first pump to prevent fluid being infused or aspirated by the second pump from entering the first fluid section of the system. Similarly, a second valve, e.g., a check valve, can be disposed in the in the catheter, in the second fluid tube, or in the second pump to prevent fluid being infused or aspirated by the first pump from entering the second fluid section of the system. In some embodiments, only one of the first and second fluid channels includes a valve. The first fluid section can be used to infuse a drug and the second fluid section can be used to infuse a fluid, e.g., drug, buffer, chaser, CSF, artificial CSF, saline, etc. The first fluid section can be used to infuse a fluid and the second fluid section can be used to aspirate a fluid. 
     The needle  302  or the catheter  304  can include a sensor  314  (e.g., a pressure sensor) mounted adjacent a distal tip of thereof. Accordingly, upon insertion of the needle  302  or catheter  304  into the patient, the sensor  314  can measure the pressure or other properties of the patient&#39;s CSF. The needle  302  or catheter  304  can also include an integrated or remote display for displaying the output of the sensor  314  to a user. In some embodiments, the display can be mounted along the length of the needle or catheter, distal to a proximal hub or other connector. The needle body can be a tubular shaft with a sharpened or angled tip. A distal end of the needle can be curved in one or more planes. 
     As shown in  FIGS. 24E-24G , the catheter  304  can be inserted through the needle  302  such that a distal end of the catheter protrudes from the needle. Alternatively, the catheter can be inserted such that it is recessed relative to the distal end of the needle, or such that the distal ends of the needle and of the catheter are flush. 
     The needle  302  can have a length in the range of about 2 inches to about 5 inches, e.g., a length of about 3.5 inches. The hub  312  can have a length in the range of about 1 inch to about 3 inches, e.g., about 2 inches. The needle  302  can have an outside diameter in the range of about 26 gauge to about 10 gauge, e.g., about 17 gauge. The catheter  304  can have an outside diameter in the range of about 0.020 inches to about 0.125 inches. The needle  302  can have an inside diameter in the range of about 0.020 inches to about 0.2 inches. The catheter  304  can be inserted through the needle  302  such that the catheter protrudes from the distal end of the needle by a protrusion distance. The protrusion distance can be in the range of about 1 mm to about 5 cm, e.g., about 1 cm. The protrusion distance can be zero such that the catheter  304  does not protrude from the needle  302 . Limiting the degree to which the catheter  304  protrudes from the needle  302  can advantageously obviate the need to thread the catheter through the intrathecal space. This can be make the delivery procedure safer and/or less invasive and reduce the level of skill required to use the system  300 . 
     The catheter  304  can have any of the features of the catheters described above.  FIGS. 25A-25D  illustrate an exemplary catheter  304  that can be used in the system  300 . The catheter  304  can include a tubular body  316  that defines one or more fluid lumens  318 . The catheter  304  can include one or more ports  320  that place the inner fluid lumen  318  of the catheter in fluid communication with the exterior of the catheter. Fluid can be infused or aspirated through the ports  320 . The illustrated catheter includes a port  320 A in the form of a helical-shaped slit.  FIG. 25B  schematically illustrates an exemplary helical-shaped slit geometry in three-dimensions. The slit  320 A can be formed in the sidewall of the catheter, in the sidewall of a reduced-diameter distal portion of the catheter, or in the sidewall of an inner tube projecting from a distal end of the catheter. In embodiments that include an inner tube, the inner tube can extend the full length of the catheter or along only a portion of the catheter length. The inner tube can be affixed to the catheter using an adhesive, sonic welding, or other techniques. Alternatively, the inner tube can be formed integrally with the main catheter body, e.g., via a molding or milling process. The catheter can include a front-facing port  320 B. The front-facing port can be defined by a circular opening formed in a distal-facing end wall of the catheter  304 . 
     While a helical-shaped slit is shown, the catheter  304  can alternatively or additionally have ports with other shapes. Exemplary port shapes include circular holes, a plurality of discrete holes arranged in a helical pattern about the catheter, cage or mesh type openings, and so forth. As shown in  FIG. 25E , a helical-shaped slit port  320 A can advantageously increase the dispersion of fluid infused through the catheter  304  into a surrounding medium. 
     The distal end of the catheter  304  can have an atraumatic geometry. For example, the catheter can include a substantially spherical or bulb-shaped portion  322  at a distal end thereof as shown. In embodiments in which the catheter  304  includes a stepped-down or reduced-diameter portion, the catheter can include a fillet or flange  324  to transition between the different diameters. For example, as shown in  FIGS. 25C-25D , a tapered transition can be formed between the reduced distal portion of the catheter and the enlarged proximal portion of the catheter. The tapered transition can be conical. The tapered transition can be convexly or concavely curved. 
     The distal portion of the catheter  304  can be formed from, coated with, or impregnated with a radiopaque, magnetic, or other image-able material. For example, a separate inner tube in which the fluid port is formed can be formed from such a material and attached to the outer catheter body. The image-able material can facilitate visualization and guidance of the tip of the catheter under fluoroscopy or other imaging techniques such as MRI, CT, PET, and the like. 
     The catheter  304  can be formed form any of a variety of materials. Exemplary materials include polyimide, PEEK, polyurethane, silicone, and combinations thereof. 
     The drug delivery system  300  can be used in a manner similar or identical to the drug delivery systems described above.  FIG. 26  illustrates an exemplary method of using the system  300 . As shown, the needle  302  can be inserted percutaneously into a patient in the lumbar region of the patient&#39;s spine, e.g., using standard lumbar puncture technique. The curved distal end of the needle  302  can help guide the distal opening of the needle into the intrathecal space IS without damaging the spinal cord SC. The needle  302  can be inserted into the intrathecal space only to a small degree, e.g., about 1 cm in to the intrathecal space. A catheter  304  can be inserted through the needle  302  to position a distal tip of the catheter within the intrathecal space. As noted above, in some embodiments, the catheter  304  only protrudes from the needle  302  by a small amount, e.g., by about 1 cm. The proximal end of the catheter  304  or the needle  302  can be coupled to a pump system  310  for infusing or aspirating fluid through the catheter or the needle. In some arrangements, the pump system includes separate drug and buffer channels, each having a respective pump. The pump system can be coupled to dual lumens of the catheter, e.g., at a bifurcated proximal portion of the catheter. In other arrangements, a first channel of the pump system can be coupled to the needle and a second channel of the pump system can be coupled to the catheter. In other arrangements, the catheter can be omitted and the pump system can include a single channel coupled to the needle, or can include multiple channels coupled to the needle. 
     A controller  104 , e.g., a programmable computer processor, or a user can control the pump system  310  to infuse and/or aspirate fluid from the patient via the catheter and/or needle. 
     In an exemplary embodiment, a drug can be infused through a first fluid channel of the system  300  and, thereafter, a chaser can be infused through the same or a different fluid channel of the system to push the drug through the intrathecal space of the patient. Exemplary chasers include drug-containing fluid, buffer fluid, artificial CSF, natural CSF previously aspirated from the patient, saline, etc. In some embodiments, the chaser can be CSF previously aspirated from the patient and the CSF can be aspirated and infused using the same syringe without removing the CSF from the syringe, thereby maintaining a closed sterile system. 
     The catheter  304  or needle  302  can include any of the features of the needle  402  described below. 
       FIG. 28A  illustrates an exemplary drug delivery system  400  that can be used for intrathecal infusion and/or aspiration of fluid. The system  400  is substantially similar to the system  300  described above, though in the system  400 , fluid is delivered or aspirated directly through the needle  402 , without inserting a catheter through the needle. The needle  402  can be coupled at a proximal end thereof to a pump system  410 . As in the systems described above, the pump system  410  can have multiple fluid channels (e.g., one channel for drug and another channel for chaser). The pump system  410  can be connected to the needle  402  by one or more fluid tubes. A hub can be formed on or coupled to the needle  402  to connect the needle to the fluid tubes. For example, a Y-connector port can be used to connect the pump system  410  to the needle  402 . The needle  402  can have various diameters and, in an exemplary embodiment, can be a 22 gauge needle. One or more valves  414  can be disposed in-line in the fluid tubes, in the needle  402 , or in the pump system  410 . The valves  414  can be one-way valves, check valves, etc. 
     The needle can have any of a variety of fluid ports formed therein. For example, as shown in  FIGS. 28A-28B , the needle  402  can include a helical slit fluid port  420 A formed adjacent a distal tip of the needle. The fluid port  420 A can be laser-cut. As another example, as shown in  FIG. 29 , the needle  402 A can have a helical inner lumen  418  disposed adjacent to a distal fluid port  420 B. The helically-shaped inner lumen  418  can facilitate turbulent flow of infusate through the distal fluid port to better disperse the fluid. The helically-shaped inner lumen  418  can be a tubular passage that defines a plurality of looped coils. The needle  402  can include a sharpened pencil tip. As another example, as shown in  FIGS. 30A-30C , the needle  402 B can include an inflatable member  426 , e.g., a balloon or membrane, disposed in a distal end of the needle. The needle  402  can include a sharpened tip. The inflatable member  426  can be initially retracted within the tip of the needle  402 , and the sharpened tip can be used to pierce the patient&#39;s dura D or other tissue to facilitate needle insertion. Once the distal tip of the needle  402  is positioned in a desired location, e.g., within the intrathecal space, the inflatable member  426  can be deployed outside of the needle, as shown in  FIG. 30B . Deployment of the inflatable member  426  can be achieved by infusing fluid through the needle  402 . The inflatable member  426  can include one or more fluid ports formed therein, through which fluid can be infused or aspirated. For example, as shown in  FIG. 30C , the inflatable member  426  can include a helical fluid port  420 A formed therein through which fluid can be infused. The inflatable member  426  can be formed from a soft material, e.g., a material softer than the material used to form the needle  402 , to define an atraumatic tip when the inflatable member is deployed. The inflatable member  426  can be formed from a flexible biocompatible material such as silicone. 
     The needle  402  can include any of the features of the catheter  304  or needle  302  described above. 
     In some embodiments, volume displacement of CSF can be used to move an infused drug through the intrathecal space of the patient. For example, fluid can be aspirated from the intrathecal space before, during, or after drug infusion to urge the drug in a desired direction within the intrathecal space. The fluid used for such volume displacement can be in the range of about 1% to about 20% of the patient&#39;s total CSF volume. The fluid can be aspirated from the patient and then subsequently re-infused. 
     The systems disclosed herein can be used for patient-specific infusion. In an exemplary patient-specific infusion method, a specific patient&#39;s CSF volume can be determined, for example by calculating or estimating. For example, a preoperative or intraoperative image of the patient can be captured. The image can be one or more MRI images of the patient&#39;s head and spine and/or entire central nervous system. Image processing routines or manual estimation techniques can be used, e.g., with correlation to a 3D anatomical model, to calculate or estimate the total CSF volume of the patient. The calculated or estimated CSF volume can be used to tailor an infusion and/or aspiration profile to that particular patient. For example, about 1% to about 20% of the calculated or estimated total CSF volume can be aspirated from the patient and re-infused behind an infused drug to urge the drug in a desired direction, e.g., cranially or caudally within the patient&#39;s intrathecal space. 
     In some embodiments, a method can include measuring the CSF head to body volume of a human using magnetic resonance imaging or other means. The method can include therapy or drug infusion performed by removal and/or infusion of 0.5 to 20% of the patient&#39;s total CSF volume. The method can include therapy or drug infusion performed by removal and/or infusion of artificial CSF, buffer solutions, or saline in conjunction with delivery of drug or therapy. The method can include delivering the drug or therapy at volume flow rates in the range of about 0.1 ml/min to about 30 ml/min. The drug and additional volume (e.g., aspirated CSF, artificial CSF, buffer, etc.) can be infused using pulsatile delivery as disclosed herein and/or using pulsatile delivery based on a physiological parameter as disclosed herein. The drug and additional volume can be infused serially or in parallel. Volume displacement and/or patient-specific drug or therapy infusion can advantageously provide better biodistribution of the infused drug. 
       FIG. 27  illustrates an exemplary method of patient-specific infusion. As shown, the method can include determining the patient&#39;s total CSF volume, aspirating a volume of CSF based on the patient&#39;s total CSF volume, and infusing a drug. 
     The infusion flow rate of the systems disclosed herein can be in the range of about 0.001 ml/min to about 50 ml/min. 
     U.S. Provisional Application No. 62/159,552 filed on May 11, 2015, U.S. Provisional Application No. 62/239,875 filed on Oct. 10, 2015, U.S. Provisional Application No. 62/303,403 filed on Mar. 4, 2016, and U.S. application Ser. No. 15/151,585 filed on May 11, 2016 are hereby incorporated herein by reference in their entirety. 
     Although the invention has been described by reference to specific embodiments, it should be understood that numerous changes may be made within the spirit and scope of the inventive concepts described. Accordingly, it is intended that the invention not be limited to the described embodiments.