阅读说明：本技术 药物递送系统和方法 (Drug delivery system and method ) 是由 P·阿南德 M·布罗菲 德普阿琼·辛格 G·埃贝尔 A·阿祖曼德 S·穆拉 A·伊斯特 于 2018-11-15 设计创作，主要内容包括：本文公开药物递送系统和方法。在一些实施例中,药物递送系统可被配置成与患者的生理参数(例如,所述患者的天然脑脊髓液(CSF)脉动或所述患者的心脏或呼吸速率)协调向所述患者递送药物。在一些实施例中,药物递送系统可被配置成使用输注和抽吸的组合以控制药物向患者递送。还公开用于在上文系统中使用的导管、控制器和其它部件,以及使用这类系统的各种方法。(Drug delivery systems and methods are disclosed herein. In some embodiments, a drug delivery system may be configured to deliver a drug to a patient in coordination with a physiological parameter of the patient, such as the patient's natural cerebrospinal fluid (CSF) pulsation or the patient's heart or respiratory rate. In some embodiments, the drug delivery system may be configured to use a combination of infusion and aspiration to control the delivery of the drug to the patient. Catheters, controllers, and other components for use in the above systems are also disclosed, as are various methods of using such systems.)

1. A catheter implantable in a body lumen of a patient, the catheter comprising:

a body extending between a proximal end and a distal end;

at least one lumen extending within the body;

a distal outlet at a distal end of the body; and

a plurality of radial outlets staggered along a length of the body and arrayed around a circumference of the body.

2. The catheter of claim 1, wherein a total cross-sectional area of the plurality of radial outlets is less than a cross-sectional area of the distal outlet.

3. The catheter of claim 1 or 2, wherein the distal outlets comprise staggered bifurcated distal outlets.

4. The catheter of claim 3, further comprising a control wire coupled to at least one of the staggered bifurcated distal outlets, the control wire actuatable to bifurcate the staggered bifurcated distal outlets in situ.

5. The catheter of claim 1 or 2, wherein the at least one lumen comprises a plurality of lumens extending within the body.

6. The catheter of claim 5, wherein the distal outlet comprises a plurality of distal outlets of the plurality of lumens disposed in a helical configuration at a distal end of the body.

7. The catheter of claim 5 or 6, wherein the plurality of radial outlets comprises a plurality of radial outlets of one or more of the plurality of lumens having varying sizes.

8. The catheter of claim 5, wherein the plurality of radial outlets comprise helical cuts in one or more arcs of side lumens of the plurality of lumens.

9. The catheter of any one of claims 5-8, wherein at least one of the plurality of lumens has a crescent-shaped or arcuate cross-section.

10. The catheter of any one of claims 5-9, wherein one of the plurality of lumens comprises a dedicated guidewire lumen configured to receive a removable guidewire therethrough.

11. The catheter of any one of claims 1-9, further comprising a steerable wire extending within the body.

12. The catheter of any of the foregoing claims, wherein the body further comprises a radiopaque marker disposed adjacent to one or more of: the distal outlet, the proximal ends of the plurality of radial outlets, or the distal ends of the plurality of radial outlets.

13. The catheter of any one of the preceding claims, wherein the body comprises a selectively expandable body.

14. The catheter of claim 13, wherein the selectively expandable body comprises an outer sheath expandable from a first, bundled configuration to a second, expanded configuration.

15. The catheter of claim 13, wherein the selectively expandable body includes a proximal portion configured to wrap around a subcutaneous port such that rotation of the port expands the body.

16. The catheter of any of the foregoing claims, further comprising a retaining mechanism to selectively retain the body at a desired location within the body lumen.

17. The catheter of claim 16, wherein the retention mechanism includes a balloon having a first inflated state in which the balloon centers the body within the body lumen and allows fluid to flow through the balloon and a second inflated state in which the balloon occludes the body lumen.

18. The catheter of claim 17, wherein the balloon is coupled to the body adjacent the proximal end to control or limit flow in a distal direction or to the body adjacent the distal end to control or limit flow in a proximal direction.

19. The catheter of claim 17, wherein the balloon comprises a plurality of simultaneously inflatable balloons to control or restrict flow between the balloons or to maintain a therapeutic agent at a specified location.

20. The catheter of any one of claims 17-19, wherein the balloon is secured to the body.

21. The catheter of claim 16, wherein the retention mechanism comprises a shape memory wire extendable from a storage position within the body to a retention position in a preformed shape to anchor the body within the body lumen.

22. The catheter of any of the foregoing claims, wherein the body comprises a multi-layer structure including an inner liner, a reinforcing layer, and an outer sleeve.

23. The catheter of claim 22, wherein the reinforcing layer comprises a braided layer or a coiled layer.

24. The catheter of claim 23, wherein the stiffening layer further comprises a steering line configured to navigate the main body within the body lumen.

25. The catheter of any one of claims 22 to 24, wherein the multilayer structure comprises a structural layer with a perforation pattern alternating with hydrophilic or nanoporous layers allowing local penetration.

26. The catheter of claim 25, wherein the structural layer comprises two structural layers defining a reservoir therebetween.

27. The catheter of claim 25 or 26, wherein the hydrophilic or nanoporous layer comprises a treatment material configured to release upon contact with a predetermined fluid or infusion pressure.

28. The catheter of any one of the preceding claims, wherein the body comprises outwardly extending longitudinal ridges forming longitudinal channels on the outer surface of the body to form flow channels externally.

29. The catheter of any one of the preceding claims, further comprising one or more doses of a therapeutic agent for treating one or more of: parkinson's disease, peroneal ataxia, canavan's disease, amyotrophic lateral sclerosis, congenital seizure, epileptic syndrome, pain, spinal muscular atrophy, tauopathy, huntington's disease, brain/spine/central nervous system tumors, inflammation, hunter's syndrome, alzheimer's disease, hydrocephalus, sanfilippo syndrome type a, sanfilippo syndrome type B, epilepsy, pre-epileptic vision disease, primary central nervous system lymphoma, primary progressive multiple sclerosis, acute diffuse encephalomyelitis, prescription for motor fluctuations in patients with advanced parkinson's disease, acute repetitive seizures, status epilepticus, enzyme replacement therapy, or neoplastic meningitis.

30. The catheter of any of the preceding claims, further comprising one or more doses of antisense oligonucleotides, adenoviruses, gene therapy (adeno-associated and non-adeno-associated viruses), including gene editing and gene conversion, oncolytic immunotherapy, monoclonal and polyclonal antibodies, stereopure nucleic acids, small molecules, methotrexate, idaolone, conotoxin, morphine, prednisolone sodium hemisuccinate, carbidopa/levodopa, tetrabenazine, benzodiazepines (diazepam and midazolam), alpha-salone or other derivatives, cyclophosphamide, iduronate (elaprase), iduronidase (aldosterone), topotecan and/or busulfan.

31. A drug delivery system comprising:

an intrathecal catheter or needle having at least one fluid lumen; and

a pump configured to inject fluid through the catheter according to a programmed infusion curve.

32. The system of claim 31, wherein the pump comprises a plurality of syringes.

33. A method, comprising:

inserting a catheter into the intrathecal space of the patient, the catheter configured to increase in length as the patient grows.

34. The method of claim 33, wherein an excess lumen of the catheter is first implanted into the port, and as the patient grows, the catheter can be manipulated to extend in length as the patient grows.

35. The method of claim 33, further comprising a distal anchoring mechanism to increase axial tension of the catheter as the patient grows.

36. A method of applying targeted infusion to the lumbar, thoracic and cervical regions of the spine and brain.

37. The method of claim 36, further comprising using infusion curves and mechanisms that target specific regions of the intrathecal space to aid in targeting.

38. A method of anchoring a catheter within a patient's spine to avoid migration of the catheter upon implantation.

39. A method of easily implanting a catheter from a lumbar region to a cervical region of a patient.

40. The method of claim 39, further comprising configuring a catheter for such easy implantation.

41. A needle configured for maximum dispersion during injection.

42. The needle of claim 41, wherein the needle comprises multiple lumens to allow for simultaneous or independent infusion of drugs and buffers.

43. A needle according to claim 41 or 42, further comprising a tubing set for establishing a connection with a fluid source.

44. The needle of any one of claims 41 to 43, having a multi-layer composite structure.

45. The needle of claim 44, wherein the multilayer composite structure comprises:

a structural layer comprising a series of perforations; and

a nanoporous or hydrophilic layer.

46. The needle of claim 45, further comprising a reservoir between the structural layer and the nanoporous or hydrophilic layer.

47. A needle according to any one of claims 41 to 46, further comprising a blunt pencil tip having a plurality of axially aligned openings or slots and a ring of three or more openings disposed around the circumference of the needle.

48. The needle of any one of claims 41 to 47, further comprising longitudinally staggered side ports.

Technical Field

Disclosed herein are systems and methods for delivering a drug to a subject (e.g., via intrathecal delivery to the cerebrospinal fluid (CSF) or subarachnoid space of the brain or spine of the subject).

Background

In many cases, it may be desirable to deliver a drug to a patient. As used herein, the term "drug" refers to any functional agent that can be delivered to a human or animal subject, including hormones, stem cells, gene therapy, chemicals, compounds, small and large molecules, dyes, antibodies, viruses, therapeutic agents, and the like.

Delivery of the drug may be accomplished systemically, or may be targeted to a specific location or a specific distribution pattern. However, targeted drug delivery can be challenging because there are many instances where the intended delivery target is not accessible or accessible in a minimally invasive manner.

The natural physiology of the patient may also present challenges to drug delivery. For example, achieving a desired or ideal drug distribution via intrathecal delivery can be difficult due, at least in part, to natural CSF flow in patients that tend to oscillate and pulsate with little net flow. Conventional techniques involving the delivery of large amounts of drug to the intrathecal space and relying on natural diffusion to dispense the drug are inefficient and may be harmful to the patient.

There is a continuing need for improved drug delivery systems and methods.

Disclosure of Invention

Drug delivery systems and methods are disclosed herein. In some embodiments, a drug delivery system may be configured to deliver a drug to a patient in coordination with a physiological parameter of the patient, such as the patient's natural cerebrospinal fluid (CSF) pulsation or the patient's heart or respiratory rate. In some embodiments, the drug delivery system may be configured to use a combination of infusion and aspiration to control the delivery of the drug to the patient. Catheters, controllers and other components for use in the above systems are also disclosed, as well as various methods of using such systems.

In some embodiments, a drug delivery system includes a catheter having at least one fluid lumen; a pump configured to infuse a fluid through a catheter; a sensor configured to measure a physiological parameter of a patient; and a controller that controls the pump to coordinate infusion of the drug through the catheter with the physiological parameter measured by the sensor.

The controller may synchronize the infusion frequency with the patient's natural intrathecal pulsation frequency as measured by the sensor. The controller may synchronize the infusion phase with the patient's natural intrathecal pulsation phase as measured by the sensor. The controller may establish a sinusoidal approximation of the patient's natural intrathecal pulsation as measured by the sensor. The controller may synchronize the infusion with the rising wave of the sinusoidal approximation. The controller may synchronize the infusion with the falling wave of the sinusoidal approximation. The sensor may be configured to measure intrathecal pressure. The sensor may include a first sensor configured to measure intrathecal pressure and a second sensor configured to measure heart rate. The controller is operable in a learning mode in which no infusion is performed and in an infusion mode in which the controller establishes a correlation between heart rate and intrathecal pressure based on the outputs of the first and second sensors; in the infusion mode, the controller coordinates infusion of the drug through the catheter with intrathecal pulsation of the patient based on an output of the second sensor. The system may include an implantable infusion port in fluid communication with the catheter and an extracorporeal syringe configured to mate with the infusion port. The catheter may include first and second fluid chambers. The controller may 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 may be configured to measure at least one of heart rate, intrathecal pressure, intrathecal pulsation rate, respiration rate, lung volume, 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 a patient; measuring a physiological parameter of a patient using a sensor; and controlling the pump with the controller to coordinate the infusion of the drug through the catheter with the physiological parameter measured by the sensor.

The method may include synchronizing the infusion frequency with the patient's natural intrathecal pulsation frequency as measured by the sensor. The method may include synchronizing the infusion phase with a patient's natural intrathecal pulsation phase as measured by the sensor. The method may include establishing a sinusoidal approximation of the patient's natural intrathecal pulsation as measured by the sensor and synchronizing the infusion with the ascending wave of the sinusoidal approximation. The method may include establishing a sinusoidal approximation of the patient's natural intrathecal pulsation as measured by the sensor and synchronizing the infusion with the descending wave of the sinusoidal approximation. The sensor may be configured to measure intrathecal pressure. The sensor may include a first sensor configured to measure intrathecal pressure and a second sensor configured to measure heart rate. The method may include establishing a correlation between heart rate and intrathecal pressure based on outputs of the first and second sensors when no infusion is performed; and coordinating the infusion of the drug through the catheter with intrathecal pulsation of the patient based on the output of the second sensor. The catheter may include first and second fluid lumens, and the method may 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 may be configured to measure at least one of heart rate, intrathecal pressure, intrathecal pulsation rate, respiration rate, lung volume, chest expansion, chest contraction, intrathoracic pressure, and intraabdominal pressure. The catheter may be inserted such that it extends along a spinal cord of a patient, wherein at least a portion of the catheter is positioned in a cervical region of the patient's spine and at least a portion of the catheter is positioned in a lumbar region of the patient's spine. The method may include delivering a plurality of different drugs through the catheter, each drug being delivered through a respective fluid lumen of the catheter. The method may include controlling the pump with the controller to draw fluid through the conduit. The catheter may include a plurality of outlet ports spaced cranially along a length of the catheter, and the method may include infusing a drug through a first port of the catheter and aspirating a fluid through a second port of the catheter, the second port being cephalad to the first port. The medication may be infused through a catheter port positioned in the cervical region of the patient's spine to advance the infused medication into the cephalad space. The method may comprise aspirating a volume of CSF from a patient; infusing a drug through a first proximal port of the catheter while drawing CSF through a second distal port of the catheter to form a drug bolus between the first and second ports; and infusing the previously withdrawn CSF at a location proximal to the bolus to propel the bolus in a distal direction. The volume of CSF aspirated from a patient may be about 10% by volume of the patient's total CSF. The catheter may be inserted through a percutaneous lumbar puncture of the patient. The infusion may 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 may be delivered to a targeted region, the targeted region being at least one of an intrathecal space of the patient, a subpial region of the patient, a cerebellum of the patient, a dental nucleus of the patient, a dorsal root ganglion of the patient, and a motor neuron of the patient. The drug may include at least one of antisense oligonucleotides, stereopure nucleic acids, viruses, adeno-associated viruses (AAV), non-viral gene therapy, exosomes (vexosomes), and liposomes. The method may include at least one of performing gene therapy by delivering a drug, performing gene editing by delivering a drug, performing gene conversion by delivering a drug, and performing non-viral gene therapy by delivering a drug. The method may include determining a total CSF volume of the patient and adjusting 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 a patient; controlling the pump with the controller to infuse the drug through the catheter; controlling the pump with the controller to draw fluid through the conduit; and controlling the infusion and the aspiration to target the drug to a target site within the patient.

The infusion may override the patient's natural CSF pulsation to push the drug toward the target site. Infusion can be coordinated with the patient's natural CSF pulsations to push the drug toward the target site. Infusion may include delivering a bolus of drug, and then performing a pulsed delivery of fluid after the bolus to urge the bolus toward the target site. The fluid may comprise 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 may be positioned in the targeted region. At least one of the infusion and aspiration may be coordinated with a physiological parameter of the patient. The physiological parameter may be at least one of heart rate, intrathecal pressure, intrathecal pulsation rate, respiration rate, lung volume, chest expansion, chest contraction, intrathoracic pressure, and intraabdominal pressure. The catheter may include first and second fluid lumens, and the method may include controlling the pump to alternately aspirate fluid through the first fluid lumen and infuse fluid through the second fluid lumen. The catheter may be inserted such that it extends along a spinal cord of a patient, wherein at least a portion of the catheter is positioned in a cervical region of the patient's spine and at least a portion of the catheter is positioned in a lumbar region of the patient's spine. The method may comprise aspirating a volume of CSF from a patient; infusing a drug through a first proximal port of the catheter while drawing CSF through a second distal port of the catheter to form a drug bolus between the first and second ports; and infusing the previously withdrawn CSF at a location proximal to the bolus to propel the bolus in a distal direction. The method may 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 may be at least one of an intrathecal space of the patient, a subdural region of the patient, a cerebellum of the patient, a nucleus pulposus of the patient, a dorsal root ganglion of the patient, and a motor neuron of the patient. The drug may include at least one of an antisense oligonucleotide, a stereopure nucleic acid, a virus, an adeno-associated virus (AAV), a non-viral gene therapy, an exosome, and a liposome. The method may include at least one of performing gene therapy by delivering a drug, performing gene editing by delivering a drug, performing gene conversion by delivering a drug, and performing non-viral gene therapy by delivering a drug. The method may include determining a total CSF volume of the patient and adjusting the infusion and/or suction based on the total CSF volume.

In some embodiments, a drug delivery catheter includes a tip having a first fluid lumen extending to a first fluid port, a second fluid lumen extending to a second fluid port, and a guidewire lumen; a pipe collector; and a body having a first fluid tube defining a first fluid lumen in fluid communication with the first fluid lumen of the tip, a second fluid tube defining a second fluid lumen 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 defining at least one internal passage in which the guidewire and the first and second fluid tubes are disposed, wherein the sheath extends from the distal end of the hub to the proximal end of the tip.

The tip may have a tapered distal end. The first and second fluid ports may be offset from a central longitudinal axis of the tip. At least one of the first and second fluid ports may be aimed perpendicularly or at an oblique angle relative to the central longitudinal axis of the tip. The first and second fluid tubes may extend uninterrupted through the manifold. The first and second fluid tubes may terminate within the manifold at respective connectors to which the proximal extension tubes may be selectively coupled. The guide wire may extend uninterrupted through the header. The first and second fluid tubes may have respective fluid connections at their proximal ends. At least one of the first and second fluid tubes may be formed of fused silica. At least one of the first and second fluid tubes may be coated in a shrink tube. The jacket may be formed of polyurethane. The sheath may include an opening formed therein that is in fluid communication with the fluid port of at least one of the first and second fluid tubes. At least one of the first and second ports may have a helical interior. At least one of the first and second ports may have an interior that tapers toward the distal tip of the port. The first fluid port may be proximal to the second fluid port. The catheter may include a auger rotatably mounted within the catheter. The conduit may include a piezoelectric transducer disposed within the conduit.

In some embodiments, a percutaneous needle device includes an elongate shaft defining at least one lumen therein; a sensor disposed at a distal tip of the elongate shaft; a display mounted to the elongated shaft configured to display an output of the sensor; and a connector disposed at a proximal end of the elongate shaft for making fluid connection with the at least one lumen.

The device may include a fluid reservoir and a flush dome in fluid communication with the lumen of the needle, wherein actuation of the flush dome effectively pumps 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 conduit, the fluid port being defined by a helical slit formed in a wall of the conduit.

The catheter may include an atraumatic distal tip defined by a substantially spherical bulb-like member. The catheter may include a second distal-facing fluid port. The helical slit may be formed in a side wall of the reduced diameter portion of the conduit. The conduit may include a tapered transition between the main body of the conduit and the reduced diameter portion of the conduit.

In some embodiments, a patient-specific infusion method comprises 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 the drug into the intrathecal space of the patient.

The method may include, after infusing the drug, infusing the aspirated patient's CSF to push the drug in a desired direction within the intrathecal space. The total CSF volume may be determined from a preoperative image of the central nervous system of the patient. The volume of CSF aspirated may range from 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.

Drawings

FIG. 1 is a schematic view of a drug delivery system;

FIG. 2 is a perspective view of a catheter that may be used with the system of FIG. 1;

FIG. 3A is a perspective view of the tip of the catheter of FIG. 2;

FIG. 3B is a cross-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 cross-sectional view of the body of the catheter of FIG. 2;

FIG. 5 is a perspective view of a header of the catheter of FIG. 2, with a portion of the header shown transparent;

FIG. 6A is a cross-sectional view of the header of FIG. 5, shown with an integrated connector;

FIG. 6B is an end view of the header of FIG. 5, shown with an integrated connector;

FIG. 7A is a plan view of a first bend curve of the guide wire of the catheter of FIG. 2;

FIG. 7B is a plan view of a second bend curve of the guide wire of the catheter of FIG. 2;

FIG. 7C is a plan view of a third bend curve of the guide wire of the catheter of FIG. 2;

FIG. 8A is a perspective partially transparent view of a tip that may be used with the catheter of FIG. 2;

FIG. 8B is a partially transparent view of the curved portion of the tip of FIG. 8A;

FIG. 9 is a perspective partially transparent view of the main body of the catheter of FIG. 2, shown with a side outlet;

FIG. 10 is a perspective and end view of a tip that may be used with the catheter of FIG. 2;

FIG. 11 is a perspective and end view of a tip that may be used with the catheter of FIG. 2;

FIG. 12 is a perspective view of a detailed partially transparent insert having a catheter that may be used with the system of FIG. 1;

FIG. 13 is a perspective view of a detailed partially transparent insert having a catheter that may be used with the system of FIG. 1;

FIG. 14 is a perspective view of a detailed partially transparent insert having a catheter that may be used with the system of FIG. 1;

FIG. 15 is a perspective view of a detailed partially transparent insert having a catheter that may be used with the system of FIG. 1;

FIG. 16 is a schematic diagram of a focused ultrasound system that may 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 screenshot of a graphical user interface that may be implemented by the controller of FIG. 17;

FIG. 20A is a perspective view of one of the systems 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, syringe and 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 medial or proximal fluid port of the catheter of FIG. 20A;

FIG. 21A is a diagram illustrating a controller of the system of FIG. 1 coordinating control of the 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 the ascending wave of the patient's natural CSF pulsation;

fig. 21C is a diagram illustrating use of the system of fig. 1 to synchronize delivery of a drug with the descending wave of the patient's native CSF pulsation;

fig. 22 is a schematic view of a drug delivery system with an intelligent lumbar puncture needle;

FIG. 23 is a schematic view of a drug delivery system with a manual pump;

fig. 24A is a schematic view of a drug delivery system;

FIG. 24B is a perspective view of the needle, manifold and catheter of the system of FIG. 24A;

FIG. 24C is a perspective view of the needle, hub and catheter of the system of FIG. 24A, shown with the catheter outside the needle;

FIG. 24D is a perspective view of the 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 the catheter of the system of FIG. 24A protruding from the needle of the system of FIG. 24A;

FIG. 24F is a perspective view of the catheter of the system of FIG. 24A protruding from the needle of the system of FIG. 24A;

FIG. 24G is a perspective view of the catheter of the system of FIG. 24A protruding from the needle of the system of FIG. 24A;

FIG. 25A is a side view of a catheter tip with a helical fluid port;

FIG. 25B is a schematic representation of the geometry of the screw 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 view of an exemplary method of use of 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 the tip of the needle of the system of FIG. 28A;

FIG. 29 is a cross-sectional side view of a tip of another needle that may be used with the system of FIG. 28A;

FIG. 30A is a schematic view of the tip of another needle that may be used with the system of FIG. 28A;

FIG. 30B is a schematic view of the needle tip of FIG. 30A with the inflatable member deployed therefrom;

FIG. 30C is a schematic view of the needle tip of FIG. 30A with fluid infusion through the inflatable member;

FIG. 31A is a schematic view of the side and cross-section of a spinal needle having distal and radial ports;

FIG. 31B is a cross-sectional view of another example spinal needle having distal and radial ports;

FIG. 32A is a side and cross-sectional schematic view of another example spinal needle with radial ports;

FIG. 32B is a cross-sectional view of another example spinal needle having a distal port;

FIG. 33 is a schematic view of an example connection for a spinal needle;

FIG. 34 is a graphical comparison between an exemplary Pulsar catheter and pump system and a manual bolus injected with a commercially available catheter;

FIG. 35 is a graphical illustration of data from a preclinical study;

fig. 36 and 37 are schematic views of an example implantable catheter having an example implantable port;

FIGS. 38A-38C are schematic views of an exemplary catheter;

39A-39C are schematic views of other example catheters;

40A-40C are schematic views of other example catheters;

41A-41C are schematic diagrams of example catheter outlet and tip configurations;

FIG. 42 is a schematic view of an example radial port for a catheter;

FIG. 43 is a schematic view of an exemplary arcuate catheter;

43B-43F are schematic diagrams of example conduit outlets and ports to disperse material;

FIG. 44 is a schematic view of an example steerable line;

FIG. 45A is a cross-sectional view of an example catheter having an expandable feature;

FIG. 45B is a schematic view of an example catheter having a flexible core;

FIG. 45C is a schematic view of an example reinforcement layer for a catheter;

FIG. 46 is a schematic view of an example catheter retention device;

FIG. 47 is a schematic view of an exemplary needle for insertion into a catheter;

FIG. 48A is a schematic diagram of an example tube set configuration;

FIGS. 48B and 48C are schematic illustrations of exemplary extension wires for a needle or catheter;

FIG. 49 is a cross-sectional view of an example catheter having a multi-layer structure;

FIG. 50 is a schematic view of a multilayer composite catheter;

FIG. 51 is a schematic view of an implantable port and connector;

FIGS. 52A and 52B are schematic diagrams illustrating an implantable port and actuator to expand the length of a catheter;

53A-57 are schematic views of example retention features for a catheter;

FIG. 58 is a schematic view of an example expandable catheter;

FIG. 59 is a cross-sectional view of an example catheter with features for real-time 3D mapping or localization;

FIG. 60 is a schematic view of an example catheter for blanket infusion;

fig. 61A is a schematic view of an example anchoring guidewire;

FIG. 61B is a schematic view of an example catheter and anchoring guidewire system; and

fig. 62A-62C are schematic views of exemplary catheters having longitudinal channels.

Detailed Description

Drug delivery systems and methods are disclosed herein. In some embodiments, a drug delivery system may be configured to deliver a drug to a patient in coordination with a physiological parameter of the patient, such as the patient's natural cerebrospinal fluid (CSF) pulsation or the patient's heart or respiratory rate. In some embodiments, the drug delivery system may be configured to use a combination of infusion and aspiration to control the delivery of the drug to the patient. Catheters, controllers and other components for use in the above systems are also disclosed, as well as 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. Features illustrated or described in connection with one exemplary embodiment may be combined with 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 drugs are injected or otherwise delivered to the central nervous system of a patient in coordination with the flow of native CSF. For example, the drug may be injected in multiple stages synchronized with the phase and/or frequency of the natural CSF pulses. The systems and methods herein may allow for more efficient delivery of drugs to patients than is the case with conventional techniques. For example, smaller amounts of drug may be delivered and still reach the target, thereby reducing costs and/or delivering possible side effects of large amounts of drug.

The systems and methods disclosed herein may be useful for applications where the intended delivery target is not accessible or accessible in a minimally invasive manner, but rather there is a more accessible and safer injection site in direct fluid communication with the intended delivery site. For example, the drug may be delivered to the intrathecal space of the patient via an injection site in the spine of the patient (e.g., lumbar region, thoracic region, cervical region, etc.) and may be transported via the intrathecal space to a targeted location cephalic of the injection site (e.g., a more cephalic region of the brain or spine). In other embodiments, the medication may be delivered to a location caudal to the injection site.

The systems and methods disclosed herein may include fully programmable customized injection and/or suction profiles that may be synchronized by real-time monitoring of patient physiological parameters, such as heart rate, CSF pressure, CSF pulsation rate, respiration rate, lung volume, chest expansion and contraction, intrathoracic pressure, intraabdominal pressure, etc. This may allow the end user to fine-tune the injection/aspiration dose per cycle, the duration and profile of each microinjection, the relative timing (or phase) of the microinjection, and other parameters. The systems and methods disclosed herein may include real-time online pressure sensing for estimating drug delivery efficiency and ensuring patient safety.

The systems and methods disclosed herein may include customized catheters having various lumen sizes, placement locations, and other characteristics. The catheter can be optimized for efficient mixing and/or directionality such that it is tailored to a particular body structure.

Fig. 1 is a schematic diagram of an exemplary drug delivery system 100. As shown, the system 100 may include a conduit 102, a controller 104, a pump or actuator 106, and one or more sensors 108. The pump 106 may be configured to pump a drug or a fluid containing a drug through the catheter 102 and into the patient 110 (e.g., into the intrathecal space of the patient). The pump 106 may also be configured to aspirate fluid from the patient. The pump 106 may be controlled by the controller 104 to synchronize or otherwise coordinate the delivery of the drug and/or the aspiration of the fluid with physiological parameters of the patient (which may be measured by the sensor 108). Exemplary physiological parameters may include heart rate, CSF pressure, CSF pulsation rate, respiration rate, lung volume, chest expansion and contraction, intrathoracic pressure, intraabdominal pressure, and the like.

An illustrative catheter 102 that may be used with the system 100 is shown in fig. 2. The catheter 102 may include a tip portion 112, a body 114, and a hub 116. A first portion 114d of the body 114 may extend between the tip 112 and the distal end of the hub 116. The second portion 114p of the body 114 may extend proximally from the manifold 116 to one or more connectors 118 or other features for coupling the catheter 102 to the system 100 (e.g., for connecting the catheter to the pump 106). The total length of the conduit 102 may be about 1 meter.

The tip 112 of the catheter 102 is shown in more detail in fig. 3A-3C. The tip 112 may comprise a generally cylindrical body having a conical, bullet-shaped, or tapered tip. The tip 112 may provide an atraumatic lead-in surface to facilitate passage of the catheter 102 through tissue or through a lumen of a patient, such as an intrathecal space. The tip 112 may include one or more fluid lumens formed therein, and corresponding one or more fluid ports through which fluid may be communicated from the fluid lumens to the exterior of the catheter, and vice versa. In the illustrated embodiment, the tip 112 includes a first fluid chamber 120A having a first fluid port 122A and a second fluid chamber 120B having a second fluid port 122B, although it should be appreciated that the tip may include any number of fluid chambers (e.g., zero, one, two, three, four, five, greater than five, etc.) and any number of fluid ports (e.g., zero, one, two, three, four, five, greater than five, etc.). The fluid ports 122A, 122B may be aimed in a substantially distal direction and may be offset from a central longitudinal axis of the tip 112, as shown. In other embodiments, the fluid ports 122A, 122B may be aimed transversely (e.g., in a direction substantially perpendicular to the central longitudinal axis of the tip 112). Slightly offsetting or laterally aiming the fluid ports from the center may advantageously reduce the risk of port occlusion during insertion or use of the catheter 102.

The catheter 102 may include a steering mechanism to facilitate remote positioning of the catheter within the patient. For example, the catheter 102 may be configured to receive a guidewire 124 through which the catheter is inserted over or steered over the guidewire. In the illustrated embodiment, the tip 112 includes a guidewire lumen 126. The guidewire lumen 126 may be a closed blind bore as shown, or may be shielded from the exterior of the tip 112. Alternatively or additionally, the catheter 102 may include one or more steering wires (not shown) terminating at the tip 112. The wires may extend proximally from the tip 112 to the proximal end of the catheter 102, where they may be selectively tensioned to steer the tip of the catheter within the patient. For example, the catheter 102 may include first and second steering wires extending longitudinally therethrough and anchored to the tip 112 at diametrically opposed locations about the outer periphery of the tip. The steering wires may extend through respective sleeves or tubes in the body 114 of the catheter 102 to the proximal end of the catheter, where a pulling force may be selectively applied thereto to steer the tip 112 of the catheter.

The tip 112 may be formed from a variety of materials, including biocompatible materials, stainless steel, titanium, ceramics, polymers, and the like. Tip 112 may be radiopaque, or may include one or more radiopaque markers to facilitate visualization under fluoroscopy or other imaging techniques.

The tip 112 may have an outer diameter of about 3French to about 5 French. The tip 112 may have an outer diameter of about 1mm to about 3 mm.

Fig. 4 is a cross-sectional view of the distal portion 114d of the catheter body 114. As shown, the body 114 may include an outer sheath 128 defining an interior passage 130. One or more fluid tubes 132A, 132B may be disposed within the internal passage, each fluid tube defining a respective fluid cavity 134A, 134B. The internal passage 130 may also contain a guide wire 124 or one or more steering wires (not shown). In the illustrated embodiment, the distal body portion 114d includes a first fluid tube 132A having a lumen 134A in fluid communication with the first fluid lumen 120A of the tip 112, a second fluid tube 132B having a lumen 134B in fluid communication with the second fluid lumen 120B of the tip, and the guide wire 124.

The sheath 128 can have a variety of cross-sectional profiles. For example, the sheath 128 may have a circular cross-section as shown defining a single internal passage 130. By way of another example, the sheath 128 may have a plurality of internal channels. Each of the fluid tubes 132A, 132B may be disposed within its own independent channel of the jacket 128, or the jacket itself may define the fluid tubes. The guidewire 124 may be disposed in a separate channel of the sheath 128 itself, and the fluid tubes 132A, 132B may be disposed in separate channels of the sheath. The guide wire channel may have an annular cross-section and the fluid tube channel may have a crescent or D-shaped cross-section.

The fluid tubes 132A, 132B may be formed from any of a variety of materials, including fused silica, polyurethane, and the like. When using the system 100 to deliver viruses, it may be advantageous to use fused silica because viruses may be less prone to adhering to the fused silica fluid tube. In some embodiments, the fluid tube for drug delivery may be formed of fused silica, and the fluid tube not for drug delivery (e.g., a buffer delivery tube or aspiration tube) may be formed of a material other than fused silica (e.g., polyurethane). The fluid tubes 132A, 132B may be coated with a shrink tube or outer jacket to provide stress and strain relief for the fluid tubes. The jacket 128 may be formed from any of a variety of materials, including polyurethane. Although described generally herein as using fluid tubes 132A, 132B to communicate fluid, the fluid tubes may be used for other purposes, such as insertion of a biopsy probe or other instrument, or insertion of sensor 108.

The inner diameter of the fluid tubes 132A, 132B may be about.005 inches to about.050 inches. The inner diameter of the fluid tubes 132A, 132B may be about.010 inches to about.020 inches. The outer diameter of the body 114 may be about 3French to about 5 French. The outer diameter of the body 114 may be about 1mm to about 3 mm.

An exemplary manifold 116 is shown in fig. 5. The manifold 116 may include respective channels for receiving the first fluid tube 132A, the second fluid tube 132B, and the guide wire 124. Each channel may include a proximal and a distal opening. The channels may merge within the body of the manifold 116 such that they each share a common distal opening. The sheath 128 of the distal body portion 114d can be received through the distal opening of the hub 116 and into the guidewire channel of the hub. The fluid tubes 132A, 132B may penetrate the sidewall of the jacket 128 within the body of the manifold 116. The hub 116 may thereby form a seal between the sheath 128 and the fluid tubes 132A, 132B, 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 header 116 may be a "punch-through" type header, wherein the first and second fluid tubes 132A, 132B extend uninterrupted completely through the header, as shown in fig. 5. Alternatively, as shown in fig. 6A-6B, the first and second fluid tubes 132A, 132B may terminate within the hub at the respective connector ports 136A, 136B. The connector ports 136A, 136B may selectively couple and decouple the proximal body portion 114p (e.g., a proximal extension tube) from the first and second fluid tubes 132A, 132B. The guidewire 124 may continue uninterrupted to extend completely through the hub 116, or it may also terminate within the hub at a connector to which the proximal guidewire extension may be selectively coupled. Any of a variety of connector types may be used to couple the fluid tube to the proximal extension tube, including zero dead volume microconnectors or fittings available from Valco Instruments co.

The proximal body portion 114p may include a sheath similar to the distal body portion 114d, or may be formed by the manifold 116, or fluid tubes 132A, 132B extending proximally from one or more extension tubes coupled to the fluid tubes 132A, 132B at the manifold 116. The proximal end of the catheter 102 may include one or more connectors 118 for making fluid connections with the fluid tubes 132A, 132B of the catheter. For example, as shown in fig. 2, the fluid tubes 132A, 132B (or proximal extension tubes as the case may be) may include a connector 118 at their proximal ends. Any of a variety of connector types may be used, including zero dead volume microconnectors or fittings available from walco instruments, houston, texas.

A guidewire 124 may be disposed within the catheter 102 and may be used to guide, steer or otherwise control insertion of the catheter into the patient.

The guide wire 124 may be cylindrical and may have a substantially straight profile. The guidewire 124 may extend completely through the catheter 102 or may terminate in a blind bore 126 formed in the tip 112 of the catheter. In use, the guide wire 124 may be inserted into the patient and guided to the target site first, and then the catheter 102 may be inserted over the guide wire to position a portion of the catheter at the target site. In other embodiments, the catheter 102 may be inserted before or simultaneously with the guidewire 124, and the guidewire may be used to steer or guide the catheter.

For example, as shown in fig. 7A-7C, the guide wire 124 may have a resting configuration that is offset from a straight line at or near the distal tip of the guide wire. In fig. 7A, the guide wire 124 has a straight distal portion 124d and a straight proximal portion 124p joined by a curved bend such that a central longitudinal axis of the distal portion extends at an oblique angle relative to a central longitudinal axis of the proximal portion. In fig. 7B, the guide wire 124 has a curved distal portion 124d joined to a straight proximal portion 124p such that a central longitudinal axis of the distal portion extends at an oblique angle relative to a central longitudinal axis of the proximal portion. In fig. 7C, the guide wire 124 has a straight distal portion 124d and a straight proximal portion 124p that meet at an angled bend such that the central longitudinal axis of the distal portion extends at an oblique angle relative to the central longitudinal axis of the proximal portion.

In use, the guide wire 124 may be used to navigate the catheter 102 through the patient by twisting the proximal end of the guide wire to turn the curved distal portion and thereby steer or aim the catheter. Although a single guidewire 124 is shown, it should be appreciated that the catheter 102 may include any number of guidewires and/or guidewire lumens. The guide wire 124 may be formed from any of a variety of materials, including shape memory metals, such as nitinol.

Any of the catheters disclosed herein may be steerable. For example, a steering mechanism may be provided to cause the distal end of the catheter 102 to be guided during insertion or at another desired time. In some embodiments, the catheter 102 may include one or more steering wires having a first end coupled to the distal tip 112 of the catheter and a second end at the proximal end of the catheter, through which a pulling force may be selectively applied to the steering wires to steer or steer the tip of the catheter in a desired direction. The steering wires may be embedded in the sidewall of the catheter 102 or may extend through the lumen of the catheter.

In some embodiments, the catheter 102 may include a coaxial steering catheter (not shown) extending therethrough. The distal tip of the steering catheter can be bent or biased toward a curved shape such that the main catheter can be steered or guided along the curve of the steering catheter as the steering catheter is deployed distally from the tip of the main catheter 102. The divert guide tube can then be retracted into the main guide tube 102 to stop the bend guide. The steering catheter may be formed of or may include a shape memory or elastic material such that the steering catheter is deformable between a generally straight configuration when retracted into the main catheter 102 and a curved or curvilinear configuration when deployed from the main catheter. The steering catheter is longitudinally translatable relative to the main catheter 102 to allow for deployment and retraction.

Any of the catheters disclosed herein may include a camera or imaging device that may be integrated with the catheter or may be inserted through the working channel of the catheter. Any of the catheters disclosed herein may include markers visible under fluoroscopy, CT, MRI, or other imaging techniques to visualize the catheter in images captured using such techniques.

The conduit 102 may be configured to withstand high internal pressures. The conduit 102 may be configured to withstand a pressure of at least about 100psi, at least about 200psi, and/or at least about 500 psi.

It will be appreciated that many variations of the catheter 102 described above are possible. For example, one or more fluid ports may be aimed sideways so that they exit the lateral side wall of the catheter. Fig. 8A-8B illustrate an exemplary catheter tip with a side-facing port. As shown, tip 112 includes a first fluid lumen 120A extending to a distally facing port 122A. The distal facing port 122A may be formed in an angled or chamfered distal face of the tip 112. Tip 112 also includes a second fluid chamber 120B that extends to a laterally facing port 122B. Tip 112 may also include a guidewire lumen for receiving the distal end of guidewire 124. In some embodiments, the central channel 130 of the sheath 128 may serve as a fluid lumen, for example for delivering a buffer or for delivering a drug. Tip 112 may include a laterally facing port 122C in fluid communication with central passage 130 of sheath 128.

The catheter 102 may include one or more fluid ports formed proximal to a tip portion 112 of the catheter, such as in a body 114 of the catheter. Fig. 9 illustrates an exemplary catheter body 114 having a side-facing port 122B. As shown, one or more of the fluid tubes 132A, 132B extending through the jacket 128 of the body 114 may terminate within the body or may otherwise have fluid ports disposed therein. The sheath 128 may have a slit or opening 122B aligned with the port of the fluid tube 132B so that fluid exiting the fluid tube may flow through the opening in the sheath or so that fluid may flow through the sheath and into the port of the fluid tube. The catheter 102 may include one or more plugs 138 disposed within the passage 130 of the sheath 128 to prevent fluid exiting or entering the fluid tube 132B from flowing proximally and/or distally within the sheath, but rather to direct fluid out of the sheath through openings or slits 122B formed therein or to direct incoming fluid into the fluid port of the tube. The plug 138 may be formed of a rigid material, an adhesive, silicone, or various other materials.

The fluid lumen of the catheter may have various internal geometries to control or direct the delivery pattern of the fluid delivered therethrough. Fig. 10 illustrates an exemplary catheter tip 112 in which one of the fluid lumens 120A has threads formed on its inner surface to define a helical or "spiral" shape. The helical shape of the fluid cavity 120A may promote turbulence of the incoming fluid, thereby promoting dispersion or even distribution of the fluid. It will be appreciated that more than one fluid chamber may have a helical tip. Fig. 11 illustrates an exemplary catheter tip 112 in which one of the fluid lumens 120A is tapered or narrowed toward the distal tip to create a nozzle. This nozzle can create a jet effect, increasing the speed of the infusate actually delivered. It will be appreciated that more than one fluid chamber may have a nozzle tip. As also shown in fig. 10-11, one or more of the fluid chambers may have a simple cylindrical tip.

As mentioned above, the catheter 102 may include any number of lumens extending therethrough. In some embodiments, a dual lumen catheter may be used. The dual lumen catheter may include an infusion lumen and a pressure sensor lumen, an infusion lumen and an aspiration lumen, two infusion lumens, and the like. In other embodiments, a three lumen catheter may be used. A three-lumen catheter may include an infusion lumen, a suction lumen, and a pressure sensor lumen, two infusion lumens and a suction lumen, three infusion lumens, and the like. Fig. 10 illustrates an exemplary three lumen catheter having an infusion lumen 120A, an aspiration lumen 120B, and a pressure sensor lumen 120C. Fig. 11 illustrates an exemplary dual lumen catheter for the infusion lumen 120A and the aspiration lumen 120B.

The conduit may include a valve system to control the direction of fluid flow therethrough. For example, the valve system may include a one-way valve on each lumen to prevent infusion into the aspiration lumen, and vice versa. The valve system may facilitate the use of a single syringe or other pump to infuse and withdraw fluids, or may facilitate the infusion and aspiration through a single lumen.

As discussed further below, the sensor 108 may be mounted to the catheter 102, integrally formed with the catheter, threaded into a lumen of the catheter, or the like. For example, the catheter 102 may include a sensor 108 embedded in the tip portion 112 of the catheter, or may include a sensor threaded through a dedicated sensor lumen of the catheter.

One or more of the fluid lumens through the catheter may have fluid ports longitudinally offset from fluid ports of other lumens of the catheter. For example, as shown in fig. 12, the catheter 102 may include a first fluid lumen 120A extending to a fluid port 122A formed at the final distal tip of the catheter. The catheter 102 may also include a second fluid lumen 120B extending to a fluid port 122B spaced a distance D apart from the distal tip of the catheter in the proximal direction. As shown, the second fluid chamber 120B may include one or more side-facing ports 122B. In other embodiments, the second fluid cavity 120B may include a distally facing port. In use, one of the fluid lumens 120A, 120B may be used to deliver a drug or other fluid, and the other fluid lumen may be used to aspirate fluid from the patient. The catheter 102 may thus be used to create a "push-pull" effect at the target site, where the drug is infused at the distal tip of the catheter via the first fluid lumen 120A, and then pulled back toward the proximal tip of the catheter by the flow of fluid aspirated through the second fluid lumen 120B. The reverse arrangement may also be used, with drug infusion through the proximal port(s) and aspiration through the distal port(s). The proximal end of the catheter 102 may have first and second connectors 118A, 118B corresponding to the first and second fluid lumens 120A, 120B, respectively. The offset fluid ports 122A, 122B may be used to coordinate delivery with physiological parameters of the patient, such as native CSF flow. An external peristaltic pump or other device may be used to drive infusion and/or aspiration. As shown, after the second lumen 120B terminates, the outer sheath 128 of the body 114 may taper inwardly to the first lumen 120A.

The catheter 102 may include features for controlling the delivery of fluid through the catheter. For example, as shown in fig. 13, the catheter 102 may include an internal auger 140. Auger 140 may have an elongated flexible shaft 142 extending through catheter 102 to the proximal end of the catheter, where it may be coupled to a motor for driving the auger in rotation. The motor may be part of the controller 104 or may be a separate component. The controller 104 may start and stop rotation of the auger 140 and/or may control the speed or direction of auger rotation to control the delivery of fluid through the fluid cavity 120 in which the auger is disposed. Auger 140 may be disposed in fluid tube 132 extending through sheath portion 128 of catheter 102. Auger 140 may also be disposed distal to the final distal end of fluid tube 132 with auger shaft 142 extending through the fluid tube. The auger 140 may thus be disposed within the sheath 128 of the catheter 102 but distal to the fluid tube 132 of the catheter. Auger 140 may advantageously control the fluid passing through conduit 102 and generate more turbulent fluid flow from the conduit. The proximal end of the catheter may have first and second connectors 118A, 118B corresponding to the first and second fluid lumens, respectively, and a third port or connector 118C through which the auger shaft 142 may extend. Auger 140 may be used to coordinate delivery with physiological parameters of the patient, such as native CSF flow.

By way of another example, as shown in FIG. 14, the catheter 102 may include an internal reciprocating piston or inner tube 144. The catheter 102 may include a fixed outer tube 128 and a slidable inner tube 144 coaxially disposed within the outer tube. The inner tube 144 may be configured to translate longitudinally relative to the outer tube 128. Inner tube 144 may include a valve 146, such as at its final distal tip. Exemplary valves include one-way valves, duckbill valves, spring-biased check valves, and the like. A seal may be formed between the inner tube 144 and the outer tube 128, for example at the proximal end of the catheter 102. In use, inner tube 144 may be loaded with a fluid containing a drug. Inner tube 144 may then be pulled proximally relative to outer tube 128 to cause the drug-containing fluid to flow through one-way valve 146 into the distal end of the outer tube. Inner tube 144 may then be pushed distally, closing the one-way valve 146 and expelling the drug-containing fluid out the distal end of outer tube 128 and into the patient. Translating tubes 128, 144 may allow a fixed or predetermined volume of infusate containing a drug to be delivered with each reciprocation of inner tube 144. The proximal ends of the outer and inner tubes 128, 144 may include connectors 118A, 118B, for example, for supplying fluid to the outer and inner tubes. The reciprocating inner tube 144 may be used to coordinate delivery with physiological parameters of the patient, such as natural CSF flow.

As another example, as shown in fig. 15, the catheter 102 may include a transducer 148, such as a piezoelectric transducer, to help control the delivery of the drug through the catheter. The transducer 148 may be formed on a flexible circuit or other substrate disposed adjacent the fluid port 122 of the catheter 102. The transducer 148 may include an electrically conductive lead or wire 150 extending proximally therefrom through the catheter 102 to the controller 104. In use, an electrical potential may be applied to the transducer 148 to induce vibration or other movement of the transducer. This movement may control the distribution of the drug from the catheter 102. For example, the transducer 148 may control the direction of infusion fluid flow as it exits the catheter 102, may control the opening or closing of the fluid port 122 of the catheter, and/or may control the volume of infusion fluid exiting the catheter. The proximal end of the catheter 102 may have a third port or connector 118C through which electrical conductors 150 of the first and second connectors 118A, 118B and transducer 148, respectively, corresponding to the first and second fluid lumens, respectively, may extend. The transducer 148 may be used to coordinate delivery with physiological parameters of the patient, such as native CSF flow.

The system 100 may include one or more transducers for delivering focused ultrasound to a patient. As shown in fig. 16, the focused ultrasound system 152 may aim the ultrasound waves away from the catheter 102 toward a location where an infusate 154 containing a drug exits. Focused ultrasound can enhance dispersion of the drug and/or control the direction and extent of drug dispersion. Focused ultrasound can be used to coordinate delivery with physiological parameters of the patient, such as native 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 the exemplary controller 104 is depicted and described herein, it should be appreciated that this is for generality and convenience. In other embodiments, the controller 104 may differ in architecture and operation from that shown and described herein. The controller 104 may be a tablet computer, mobile device, smartphone, laptop computer, desktop computer, cloud-based computer, server computer, or the like. One or more portions of the controller 104 may be implanted in the patient. Delivery control software may be implemented on the controller 104. The software may be carried out on a local hardware component (e.g., a tablet, smartphone, laptop, etc.) or may be carried out remotely (e.g., on a communications server coupled with the controller or a cloud-connected computing device).

The illustrated controller 104 includes a processor 156 that controls operation of the controller 104, such as by executing embedded software, operating systems, device drivers, application programs, and the like. Processor 156 may include any type of microprocessor or Central Processing Unit (CPU), including a programmable general-purpose or special-purpose processor and/or any of a variety of proprietary or commercially available single or multi-processor systems. As used herein, the term processor may refer to microprocessors, microcontrollers, ASICs, FPGAs, PICs, processors that read and interpret program instructions from internal or external memory or registers, and the like. The controller 104 also includes a memory 158 that provides temporary or permanent storage for code executed by the processor 156 or data processed by the processor. The memory 158 may include Read Only Memory (ROM), flash memory, one or more Random Access Memories (RAM), and/or a combination of memory technologies. The various components of the controller 104 may be interconnected via any one or more separate traces, physical buses, communication lines, etc.

The controller 104 may also include an interface 160, such as a communication interface or I/O interface that may enable the controller 104 to communicate with a remote device (e.g., other controller or computer system) over a network or communication bus (e.g., a universal serial bus). The I/O interface may facilitate communication between one or more input devices, one or more output devices, and various other components of the controller 104. exemplary input devices include touch screens, mechanical buttons, keyboards, and pointing devices. the controller 104 may also include a storage device 162, which may include any conventional medium for storing data in a non-volatile and/or non-transitory manner. the storage device 162 may thus maintain data and/or instructions in a permanent state (i.e., retain the values despite interrupting power to the controller 104). the storage device 162 may include one or more hard disk drives, flash drives, USB drives, compact disk drives, various media disks or cards, and/or any combination thereof, and other components that may be directly connected to the controller 104 or remotely connected thereto (e.g., via the communication interface 104 may also include a controller 104, and may include a power supply 164, a display for example, a display for displaying an AC display on a display such as a display, a.

The various functions performed by the controller 104 may be described logically as being performed by one or more modules. It should be understood that such modules may be implemented in hardware, software, or a combination thereof. Further, it should be appreciated that when implemented in software, the modules may be part of a single program or one or more separate programs, and may be implemented in a variety of contexts (e.g., as part of an embedded software package, operating system, device driver, standalone application, and/or combinations thereof). Further, software embodying one or more modules may be stored as a executable program on one or more non-transitory computer-readable storage media. The functions disclosed herein as being performed by a particular module may also be performed by any other module or combination of modules, and the controller may include fewer or more modules than illustrated and described herein. Fig. 18 is a schematic diagram of the modules of an exemplary embodiment of the controller 104.

As shown in fig. 18, the controller 104 may include a sensor input module 168 configured to receive information from the sensor(s) 108. The sensor input module 168 may read and interpret output signals supplied from the sensor 108 to the processor 156, for example, via a general purpose input output pin of the processor. The sensor input module 168 may optionally perform various processing of the sensor signal, such as frequency detection, phase detection, de-dithering, analog-to-digital conversion, filtering, and so forth.

The controller 104 may 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., auger, piston, transducer, ultrasound system, etc.). For example, when an "infusion" command is issued, delivery control module 170 may cause power to be supplied to pump 106 to begin pumping infusate through catheter 102, or cause an electronically actuated valve to open such that infusate stored under pressure is placed in fluid communication with and flows through the catheter. In some embodiments, the delivery control module 170 may be configured to shut off power to the pump 106 or close the valve when the pressure sensor indicates that the pressure in the system has reached a predetermined threshold amount. When a "pump" command is issued, delivery control module 170 may cause power to be supplied to pump 106 to begin pumping fluid out of catheter 102.

The controller 104 may 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 may include infusion parameters, patient information, treatment protocols, and the like as discussed further below.

Controller 104 may also include a display module 174 configured to display various information to a user on display 164, such as graphical or textual user interfaces, menus, buttons, instructions, and other interface elements. The display module 174 may also be configured to display instructions, warnings, errors, measured values, and calculated values.

Fig. 19 illustrates an exemplary graphical user interface 176 that may be displayed to a user by the display module 174 and by which a user may supply information to the user input module 172. The illustration interface 176 is configured for use with a pump system 106 that includes first and second motors or linear actuators operable to apply forces to respective syringe pumps for delivering infusate to the catheter 102 and for withdrawing or aspirating fluid from the catheter.

The user interface 176 may include a motor communication board 178 for displaying various information associated with the motor. This information may include the connection status of the motor, the IP or other software address of the motor, and the motor communication frequency or update time. The user may interact with the motor communication board 178 to select or change the motor address and update time.

The user interface 176 may include a motor settings board 180 for adjusting various motor settings and for displaying current settings to the user. The motor settings board 180 may include controls for motor speed, motor acceleration, distance of syringe travel as a function of motor step distance, current motor position, infusion frequency, infusion amplitude, infusion rate, infusion phase, and the like.

The controller 104 may be configured to control various infusion and/or aspiration parameters to achieve customized delivery. This may allow for adjustment of delivery based on the therapeutic application. Exemplary parameters that may be controlled by the controller 104 include infusion type, infusion rate, infusion volume, time between infusions, oscillation rate, infusion and aspiration rate, infusion phase timing, aspiration type, aspiration rate, time between aspirations, aspiration volume, and the like.

The pump or actuator system 106 may be configured to supply drugs or drug-containing fluids to the catheter 102 and/or to aspirate fluids from the catheter. The system 106 may include one or more pumps. For example, the system 106 may include a plurality of pumps, each associated with and in fluid communication with a corresponding lumen of the catheter 102. The pumps may also be associated with and in fluid communication with respective reservoirs for holding a volume of fluid. In some embodiments, system 106 may include first and second syringe pumps coupled to an electronic linear actuator configured to advance or retract the plunger of the syringe pump in response to control signals received from controller 104. In some embodiments, the system 106 may include a peristaltic pump, auger pump, gear pump, piston pump, balloon pump, or the like. One or more portions of the system 106 may be implanted in a patient. The system 106 may include any of a variety of implantable or extracorporeal pumps. In some embodiments, the system 106 may include a fully implanted programmable pump and a fully implanted fluid reservoir containing the fluid to be delivered using the system. In some embodiments, all of the systems 106 may be implantable, for example, to facilitate chronic treatment methods.

The sensor 108 may 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 volume sensors, chest expansion and contraction sensors, intrathoracic pressure sensors, intraabdominal pressure sensors, and the like. One or more of the sensors 108 may be implanted in the patient. One or more of the sensors 108 may be mounted on, inserted into, or formed in or on the catheter 102. Sensor 108 may also be remote from catheter 102. In some embodiments, the sensors 108 may include a pressure sensor disposed in or on the catheter 102 for measuring CSF pressure adjacent the catheter and an ECG sensor for measuring the patient's heart rate. The sensors 108 may be connected (via wires or via a wireless connection) to a sensor input module 168 of the controller 104.

As mentioned above, one or more, and in some embodiments all, of the components of the delivery system 100 may be implanted in a patient. Some or all of the graft delivery system 100 may facilitate chronic or long-term drug delivery (e.g., over a period of days, weeks, months, or years) via non-invasive or outpatient procedures.

Fig. 20A-20B illustrate catheter 102 fully implanted in a patient. As shown, the catheter 102 may be configured for positioning within a patient's intrathecal space and may extend substantially the entire length of the spine or along any portion thereof. The catheter 102 may include one or more fluid lumens. The catheter 102 may also include one or more fluid ports. In some embodiments, the catheter 102 may include multiple fluid chambers, where each of the multiple fluid chambers has its own respective fluid port. In the illustrated embodiment, the catheter 102 includes three fluid chambers and three corresponding fluid ports 122P, 122M, and 122D. The conduit 102 may also include one or more sensors 108 (e.g., pressure sensors). In the illustrated embodiment, each of the fluid ports 122P, 122M, 122D includes a sensor 108P, 108M, 108D mounted adjacent or in proximity thereto. The proximal end of the catheter 102 may be coupled to a fully implanted, percutaneous, or extracorporeal infusion port 182 through which fluid may be delivered to (or removed from) various lumens of the catheter, and through which one or more sensors 108 on the catheter may be coupled to the controller 104 or other device. A quick connector system 184 may be used to couple the catheter 102 to the infusion port 182. The microconnector 184 may include an air and/or bacterial filter and may be a zero dead volume connector. The pump 106 and controller 104 may be mounted together in a chassis or housing 188, as shown in fig. 20C, which may be coupled to a syringe 190 configured to mate with the infusion port 182. The syringe 190 may include a magnetic alignment feature 186 for ensuring proper alignment of the syringe relative to the subcutaneous infusion port 182.

As shown in fig. 20D, the distal or rostral/cervical tip of the catheter 102 may have a modified shape to promote turbulent flow therethrough (e.g., a helical or spiral cavity or fluid port 122D as described above). Any of a variety of other shapes may be used. The other ports 122M, 122P may be similarly configured, may have a simple annular cross-section as shown in fig. 20E, or may have any other configuration described herein.

The system 100 illustrated in fig. 20A-20E may be used in any of a variety of ways for acute and/or chronic applications.

For example, the catheter 102 may be used to deliver three different drugs (e.g., one drug through each different lumen of the catheter).

By way of another example, the catheter 102 may be used to deliver different drugs locally to different regions of the spine.

As another example, the catheter 102 may be used to deliver the same drug in a substantially instantaneous distribution along the entire spine.

In another example, one port of the catheter 102 may be used for aspiration and the other for infusion to pull the infused fluid through the spinal canal. In some embodiments, fluid may be infused through the lower lumbar port 122P and fluid may be aspirated through the neck port 122D to "pull" the infused fluid up the spine.

In another example, fluid may be infused through a port 122D disposed in the cervical region of the patient's spine to propel the infused drug into the cephalad space.

By way of another example, the catheter 102 may be used to substantially contain an infused drug to a given area of the spine. In some embodiments, fluid may be infused through the lower lumbar port 122P and fluid may be withdrawn from the middle lumbar port 122M to hold the infused drug between the two ports 122P, 122M in the lumbar region of the patient's spine.

In an exemplary method, infusion and aspiration via multiple lumens and ports may be staged or combined in sequence to create and advance large volumes of bolus at improved, controlled and convenient rates. The method may include simultaneous aspiration/infusion between intentionally spaced ports. Delivery may be enhanced by a preparation step that removes a safe amount of CSF when the bolus is currently moved to be replaced in a later procedural step. The method may include a final phase of synchronized pulsatile infusion. The methods may allow for more rapid formation of large boluses, may allow for controlled dosing, and/or may allow for the delivered bolus to be closer to the brain or other targeted site. The method may be performed using a catheter that tapers from a proximal end toward a distal end. A tapered catheter profile in which the catheter diameter decreases distal to each port may enable the catheter to be longer, easier to introduce/navigate, and have means to reach significantly closer to the target site. Port design and location may be optimized based on dose and other factors. The catheter may be placed such that fluid exiting the port flows against the patient anatomy (e.g., blind lumen tip, lumen sidewall, or lumen constriction) to promote turbulent flow of the infusate as it exits the catheter. In an initial step, a volume of patient CSF may be drawn through one or more ports of the catheter. In an exemplary embodiment, about 10% by volume of the patient's CSF may be drawn through the catheter and stored in the reservoir. The amount of CSF aspirated may be based on a clinically determined safety level. In a subsequent delivery step, CSF may be aspirated from the patient through the distal fluid port 122D of the catheter 102 while the drug is simultaneously infused into the patient through the catheter's medial port 122M. This may result in the formation of a bolus of drug between the intermediate and distal ports 122M, 122D. The ports may be positioned along the length of the catheter to define bolus sizes or doses. In the advancing step, the drug bolus may be advanced within the patient. This may be accomplished by infusing into the patient previously aspirated CSF from the reservoir through the proximal port 122P of the catheter 102. This infusion may push the bolus distally toward the target site and may continue until normal or safe CSF pressure is reached within the patient. Although in the above examples previously aspirated CSF is used to advance the bolus, other fluids, such as drug-containing fluids, may be used instead or in addition. Infusion of CSF and/or drug-containing fluid may be performed in a pulsed manner in coordination with one or more physiological parameters of the patient before, during, or after advancement of the bolus. The above method may also be performed using only the proximal port 122P and the distal port 122D. The proximal, intermediate, and distal ports 122P, 122M, 122D may be spaced along the length of the spine as shown in fig. 20A, or may be all contained in discrete regions of the spine (e.g., cervical, thoracic, lumbar, etc.).

The systems disclosed herein may be used in any of a variety of drug delivery methods.

In an illustrative method, the infusion pump 106 can be configured to pump a drug or drug-containing fluid through the catheter 102 and into the patient (e.g., into the intrathecal space of the patient). The catheter 102 may be inserted into the patient at any of a variety of locations. For example, a needle may be used to create a percutaneous puncture in a patient. The puncture may be made in the lumbar region of the spine, or in any other region of the spine, such as the cervical region between C1 and C2. The needle may have a curved distal tip that helps to steer the catheter 102 to be parallel to the spinal cord. The catheter 102 may be inserted through a needle and guided along the spinal cord through the intrathecal space. The infusion may be performed close to percutaneous puncture, or the catheter 102 may be advanced a distance within the patient. In some embodiments, the catheter 102 may be inserted in the lumbar region and advanced to the cervical spine or to the cisterna magna. The infusion may be performed at any point along the length of the catheter 102. Fluid may be infused from the distal tip of the catheter 102 (e.g., in the cervical region of the spine), the catheter may be withdrawn proximally, and additional infusions may be performed at more caudal locations (e.g., in the lumbar region of the spine).

The pump 106 may synchronize or otherwise coordinate the delivery of the drug with the patient's natural CSF flow or pulsation, or other physiological parameters of the patient (e.g., heart rate, respiration rate, lung volume, chest expansion and contraction, intrathoracic pressure, intraabdominal pressure, etc.), as controlled by the controller 104. The infusion curve can be adjusted to drive the infusion fluid to the target site beyond the natural CSF pulsation. Alternatively or additionally, the adjustable infusion profile is coordinated with the native CSF pulsation and leveraged to move the infusion toward the target site.

Readings from the pressure sensor 108 may be received by the controller 104, which may perform signal processing on the sensor output to determine various characteristics (e.g., phase, rate, magnitude, etc.) of the patient's CSF flow. Controller 104 may then control pump 106 based on these measured characteristics to deliver the drug in coordination with the natural CSF flow, optionally synchronizing delivery in real time. For example, as shown in the upper portion of fig. 21A, the controller 104 may convert the measured pulsed flow of CSF into a sinusoidal approximation. The controller 104 may 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 pulsations.

In some cases, the pressure sensed by the pressure sensor 108 may be affected by infusion through the catheter 102. Thus, it may be desirable to have another way of detecting or evaluating CSF flow. Thus, in some embodiments, the system 100 may initially operate in a "learn" mode, in which no infusion is performed, and the controller 104 establishes a correlation between CSF pulsation and heart rate (e.g., as detected by the ECG sensor 108 in communicative coupling with the controller). Generally, CSF pulsations track heart rate with slight delay. Once the correlation is established, the system 100 may operate in an "infusion" mode, in which infusion fluid is delivered through the catheter 102, and CSF pulsation is detected or estimated based on the measured heart rate (instead of or in addition to detecting or estimating CSF pulsation based on the pressure sensor 108 output). In other words, the system 100 can interpolate or estimate CSF flow based on ECG output without having to rely on pressure sensor output. This may allow the pressure sensor to be used for other purposes, such as monitoring infusion pressure to allow the controller 104 to automatically adjust delivery to a targeted pressure or pressure range.

In one example of the use of the system described herein, the drug may be delivered to the intrathecal space via a simple rapid injection (rapid infusion of a volume of fluid) which then only slowly diffuses along the spinal column.

In another example, a bolus injection may be performed to deliver the drug, and then the system may be used to generate a pulse after the bolus by varying the oscillation/pulsation rate to override the native CSF pulse and move the bolus more rapidly toward the targeted location (e.g., brain). Pulsatility can be produced by repeatedly drawing or aspirating a volume of CSF and then pumping that same volume back into the patient to produce pulses.

In another example, infusion of the drug itself may be used to create a pulsatile effect to push the drug along the intrathecal space. In this example, a first volume of drug (e.g., 0.1ml) may be infused, and then a second, smaller volume (e.g., 0.05ml) may be withdrawn. This can be repeated to produce a pulse with a net infusion at 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 should be appreciated that any ratio may be used. In addition, the rate of infusion and withdrawal (e.g., by rapid infusion and slow withdrawal) can be controlled to produce a burst of fluid toward the targeted location (e.g., the top of the spine).

In the devices and methods disclosed herein, infusion and/or aspiration may be coordinated with one or more physiological parameters of the patient (e.g., native CSF flow, heart rate, respiratory rate, etc.).

The direction of drug distribution at the intrathecal target site may be controlled, at least to some extent, based on the timing of drug delivery relative to the timing of CSF flow. For example, infusion synchronized with an ascending wave of CSF flow may be more distributed cephalad as shown in fig. 21B, while infusion synchronized with a descending wave of CSF flow may be more distributed caudally of the spinal canal as shown in fig. 21C.

In some embodiments, a dual or multi-lumen catheter may be used for alternating, repeated infusions and aspirations, which may further enhance drug distribution.

The systems and methods disclosed herein may provide improved means for delivering drugs to the intrathecal space compared to traditional lumbar bolus injections that do not effectively (if at all) reach the distal portion of the spinal canal or brain.

While intrathecal delivery is generally described in the examples given above, it is to be understood that the systems and methods herein may be used for other applications, with appropriate modification of size or other parameters as will be appreciated by one of ordinary skill in the art. For example, the systems and methods disclosed herein may be used for intra-arterial or intravenous delivery. Such systems and methods may include infusion and/or aspiration coordinated with one or more physiological parameters of the patient (e.g., native CSF flow, heart rate, respiratory rate, etc.).

In some embodiments, the drug may be delivered in a non-pulsatile manner and/or not necessarily in coordination with the physiological parameters of the patient. For example, alternating or otherwise coordinating aspiration and infusion may be used to deliver drugs to a targeted site. By way of another example, a drug may be infused, and then a buffer may be infused post-drug to enhance distribution or move the drug toward the target site.

An exemplary method may include inserting at least a portion of a catheter into a patient and delivering a drug to a targeted region of the patient. At least a portion of the catheter may be positioned in the targeted region. The drug may be delivered in a pulsatile manner. The drug may be delivered in coordination with physiological parameters of the patient, such as the patient's natural CSF flow and/or the patient's heart rate.

The target region may be an intrathecal space of the patient. The targeted region may 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 targeted region may be the cerebellum of the patient. The targeted region may be the nucleus pulposus of the patient. The targeted region may be a dorsal root ganglion of the patient. The targeted region may be a motor neuron of the patient. The drug may comprise an antisense oligonucleotide. The drug may comprise a stereopure nucleic acid. The drug may comprise a virus. The drug may comprise an adeno-associated virus (AAV). The medicament may comprise non-viral gene therapy. The drug may include exosomes. The drug may comprise a liposome. The method may comprise performing gene therapy by delivering a drug (e.g., by delivering a virus, such as AAV). The method may comprise performing gene editing by delivering a drug (e.g., by delivering a virus, such as AAV). The method may comprise performing gene conversion by delivering a drug (e.g., by delivering a virus, such as AAV). The method may comprise performing non-viral gene therapy by delivering a drug (e.g. by delivering exosomes and/or liposomes).

In some embodiments, the method may include determining a total CSF volume of the patient and adjusting delivery based on the total CSF volume. For example, MRI or other imaging techniques with or without contrast may be used to assess the total CSF volume of a patient. The delivery of the drug may then be adjusted based on the measured volume. For example, a larger volume of buffer is used for patients with higher total CSF volumes, and a smaller volume of buffer may be used for patients with smaller total CSF volumes. By way of further example, infusion amplitude, infusion rate, aspiration volume, aspiration amplitude, and other parameters may be varied based on the measured total CSF volume.

The infusion volume may be in the range of about 0.05m L and about 50m L the infusion rate may be in the range of about 0.5m L/min to about 50m L/min.

The following are exemplary drug delivery methods that may be performed using the systems disclosed herein:

example a:

alternate pulsed infusion of drug (pump 1) and buffer/saline (pump 2)

The total volume of the medicine is 2.2m L

Total volume of buffer solution 4.4m L

Infusion rate of two pumps 15m L/min

And (3) circulation: 10 cycles in the lumbar region and then 10 cycles in the cisterna magna

Time between cycles: 100 milliseconds

Infusion describes that in the lumbar region, pump 1 infuses 0.11m L at 15m L/min, 100ms pauses, pump 2 infuses 0.22m L at 15m L/min, 100ms pauses (cycle 1), this repeats a total of 10 cycles in the lumbar region the catheter is threaded up to the cerebellum medullary canal pump 1 infuses 0.11m L at 15m L/min, 100ms pauses, pump 2 infuses 0.22m L at 15m L/min, 100ms pauses (cycle 1), this repeats a total of 10 cycles in the cerebellum medullary canal.

Example B:

alternate pulsed infusion of drug (pump 1) and buffer/saline (pump 2)

The total volume of the medicine is 3m L

Total volume of buffer solution 20m L

The infusion speed of the two pumps is 4m L/min

And (3) circulation: 13 cycles in the thoracic region

Time between alternating pumps 1 to 2: 1000 milliseconds

Time between cycles (pump 2 to pump 1): 5000 milliseconds

Infusion describes that in the lumbar region, pump 1 infuses 0.231m L at 4m L/min, pausing for 1000ms, pump 2 infuses 2.0m L at 4m L/min, pausing for 5000ms (cycle 1). this is repeated for a total of 13 cycles in the thoracic region.

Example C:

alternate pulsed infusion of drug (pump 1) and buffer/saline (pump 2)

The total volume of the medicine is 5m L

Total volume of buffer solution 8m L

Infusion rate of Pump 1: 37m L/min

Infusion rate of Pump 2 20m L/min

And (3) circulation: in the chest region for 5 cycles

Time between cycles: 10 milliseconds

Infusion describes that in the lumbar region, pump 1 infuses 1m L at 37m L/min, pausing for 10ms, pump 2 infuses 1.6m L at 30m L/min, pausing for 100ms (cycle 1).

Fig. 22 illustrates a drug delivery system 200 including a lumbar puncture needle 292. The needle 292 can include a sensor 294 (e.g., a pressure sensor) mounted adjacent the distal tip of the needle. Thus, upon insertion of the needle 292 into the patient 210, the sensor 294 may measure the pressure or other characteristic of the patient CSF. The needle 292 may 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 may be mounted along the length of the needle 292 distal to the proximal luer or other connector 298 of the needle. The needle body 292 may be a tubular metal shaft with a sharp or angled tip. The fluid tube may be coupled to the needle 292 and to the programmable pump 106, for example, via a proximal connector 298. A controller 104 of the type described above may be programmed to control the pump 106 to deliver fluid through the needle 292 in a pulsed manner, for example, in coordination with physiological parameters of the patient. The needle 292 may be used to deliver drugs, deliver buffers, and/or aspirate fluids. In some embodiments, a catheter 102 of the type described above may be inserted through the needle 292 and fluid delivery or aspiration may be performed through the catheter.

As shown in fig. 23, a manual pump 206 may be provided in place of or in addition to the programmable pump 106 and controller 104 shown in fig. 22. As shown, the first fluid cavity of the needle 292 (or catheter 102 inserted through the needle) may be coupled to a first pump 206A comprising a first reservoir and a first flush dome. Similarly, the second fluid cavity of the needle 292 (or catheter 102 inserted through the needle) may be coupled to a second pump 206B comprising a second reservoir and a second flush dome. A user may apply manual finger pressure to the first and second flush domes to selectively force fluid contained in the first and second reservoirs into the patient. Thus, the manual actuation rate and actuation pressure of the user may indicate the infusion frequency and volume. The user may thus manually pulse delivery. The flush dome may be configured such that each successive actuation of the dome delivers a fixed and predetermined volume of fluid. For example, each push of a flush dome may be configured to deliver 0.1ml of fluid. In some embodiments, one of the reservoirs may be filled with a buffer solution and the other reservoirs may be filled with a solution containing a drug.

Fig. 24A-24G illustrate a drug delivery system 300 that may include a needle 302 and a catheter 304 insertable through the needle. Needle 302 may be a lumbar puncture needle. The catheter 304 may be a single lumen catheter or a multi-lumen catheter. For example, a double lumen catheter that bifurcates at the proximal portion of the catheter as shown may be used. The fluid tube 306 may be coupled to the conduit 304, for example, via one or more proximal connectors 308, and to a programmable pump system 310. Needle 302 or catheter 304 may also be directly connected to pump system 310.

In some embodiments, pump system 310 may include first and second pumps configured to infuse and/or aspirate fluid through the lumens of respective conduits 304. Any of a variety of pumps may be used, including a linear actuator syringe pump of the type shown in fig. 24A. A controller 104 of the type described above may be programmed to control the pump 310 to deliver fluid through the catheter 304 in a pulsed manner, for example, in coordination with physiological parameters of the patient. The catheter 304 may be used to deliver drugs, deliver buffers or other fluids, and/or aspirate fluids. In some embodiments, the catheter 304 may be omitted and fluid may be infused directly through the needle 302 and/or aspirated directly through the needle. One or more of the fluid connections are made, wherein the catheter 304 may be replaced with or in addition to the needle 302. For example, the fluid tube through which the drug is delivered may be directly coupled to the catheter 304 to deliver the drug through the catheter, and the fluid tube through which the buffer, bolus, or other fluid is delivered may be directly coupled to the needle 302 to deliver the fluid through the needle.

The needle 302 may be defined by a hollow tubular body configured to receive a catheter and/or fluid therethrough. Needle 302 may be a lumbar puncture needle sized and configured for insertion into the intrathecal space through a lumbar insertion point. The needle 302 may have a curved distal tip configured to naturally steer the needle into the intrathecal space when the needle is inserted into a patient in the lumbar region of the spine. An opening may be formed in the distal tip of the needle 302 through which an inserted catheter 304 may extend.

The proximal end of the needle may be coupled to a fluid hub 312. As shown in fig. 24B, header 312 may be a "W" header. Hub 312 may include multiple ports. Hub 312 may include a distal port to which needle 302 may be attached and placed in fluid communication with the hub. Concentrator 312 may include one or more proximal ports. The proximal port may direct catheter 304 to be inserted into hub 312 into the central lumen of needle 302. The proximal ports may attach the manifold 312 to a respective fluid line and place the manifold in fluid communication with the fluid line. Fluid lines may be used to direct fluid into the manifold 312 and through the needles 302 attached thereto. The proximal and distal ports of hub 312 may be luer type connectors or zero dead volume connectors. As shown in fig. 24B, the manifold 312 may include a distal port attached to the needle 302 and a proximal port through which the dual lumen catheter 304 is inserted to guide the catheter through the needle. Dual lumen catheter 304 may be split or bifurcated into first and second fluid lines at a location proximal of manifold 312, e.g., for carrying medication and buffer, respectively. Hub 312 may include one or more additional ports through which fluid may be introduced into needle 302 or withdrawn from needle 302. These ports may be used to deliver drugs or buffers to the needle 302 or aspirate fluids from the needle, instead of or in addition to using the catheter 304.

As shown in fig. 24C-24D, the manifold 312 may be a "Y" manifold. Hub 312 may include a distal port attached to needle 302 and a proximal port through which dual lumen catheter 304 is inserted to guide the catheter through the needle. Dual lumen catheter 304 may be split or bifurcated into first and second fluid lines at a location proximal of manifold 312, e.g., for carrying medication and buffer, respectively. Hub 312 may include one or more additional ports through which fluid may be introduced into needle 302 or withdrawn from needle 302. These ports may be used to deliver drugs or buffers to the needle 302 or aspirate fluids from the needle, instead of or in addition to using the catheter 304.

In some embodiments, the manifold may be omitted and fluid may be delivered directly to the needle 302 or pumped from the needle 302. For example, needle 302 may be directly attached to pump system 310 via one or more fluid lines, or catheter 304 may 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 may include one or more valves to control or restrict fluid flow through the system. For example, the system 300 may include check valves 314 disposed in line with respective fluid paths from the pump system 310 to the patient to separate the paths from each other in a single direction or in both directions. In an exemplary arrangement, the system 300 may include first and second independent fluid sections or channels. The first fluid section or channel may include a first pump configured to deliver a first fluid through the first fluid tube and through the first fluid lumen of the catheter 304. The second fluid section or passage may include a second pump configured to deliver a second fluid through the second fluid tube and through the second fluid lumen of the catheter 304. A first valve (e.g., a check valve) may be disposed in the conduit, in the first fluid tube, or in the first pump to prevent fluid infused or drawn by the second pump from entering the first fluid section of the system. Similarly, a second valve (e.g., a check valve) may be disposed in the conduit, in the second fluid tube, or in the second pump to prevent fluid infused or drawn by the first pump from entering the second fluid section of the system. In some embodiments, only one of the first and second fluid passages comprises a valve. The first fluid section may be used for infusing a drug and the second fluid section may be used for infusing a fluid, such as a drug, a buffer, a chaser, CSF, artificial CSF, saline, and the like. The first fluid zone may be used for infusion of fluid and the second fluid zone may be used for aspiration of fluid.

The needle 302 or catheter 304 may include a sensor 314 (e.g., a pressure sensor) mounted adjacent to its distal tip. Thus, upon insertion of the needle 302 or catheter 304 into a patient, the sensor 314 can measure the pressure or other characteristic of the patient's CSF. The needle 302 or catheter 304 may also include an integrated or remote display for displaying the output of the sensor 314 to the user. In some embodiments, the display may be mounted along the length of the needle or catheter distal to the proximal hub or other connector. The needle body may be a tubular shaft having a sharp or angled tip. The distal tip of the needle may be curved in one or more planes.

As shown in fig. 24E-24G, a catheter 304 may be inserted through the needle 302 such that the distal tip of the catheter protrudes from the needle. Alternatively, the catheter may be inserted such that it is recessed relative to the needle, or such that the needle and the distal tip of the catheter are flush.

The length of the needle 302 may be in the range of about 2 inches to about 5 inches, for example about 3.5 inches in length. The length of header 312 may be in the range of about 1 inch to about 3 inches, for example about 2 inches. The outer diameter of the needle 302 may be in the range of about 26 gauge to about 10 gauge, such as about 17 gauge. The outer diameter of the catheter 304 may be in the range of about 0.020 inches to about 0.125 inches. The inner diameter of the needle 302 may be in the range of about 0.020 inches to about 0.2 inches. A catheter 304 may be inserted through the needle 302 such that the catheter protrudes a protruding distance from the distal tip of the needle. The protrusion distance may be in the range of about 1mm to about 5cm, for example about 1 cm. The protrusion distance may be zero such that the catheter 304 does not protrude from the needle 302. Limiting the extent to which the catheter 304 protrudes from the needle 302 advantageously eliminates the need to thread the catheter through the intrathecal space. This may make the delivery procedure safer and/or less invasive and reduce the level of skill required to use the system 300.

The catheter 304 may have any of the features of the catheters described above. Fig. 25A-25D illustrate an exemplary catheter 304 that may be used in the system 300. The catheter 304 may include a tubular body 316 defining one or more fluid lumens 318. The catheter 304 may include one or more ports 320 that place the internal fluid lumen 318 of the catheter in fluid communication with the exterior of the catheter. Fluid may be infused or aspirated through the port 320. The illustrated catheter includes a port 320A in the form of a helical slit. Fig. 25B schematically illustrates an exemplary spiral slit geometry in three dimensions. The slit 320A may be formed in the sidewall of the catheter, the sidewall of the reduced diameter distal portion of the catheter, or the sidewall of the inner tube protruding from the distal tip of the catheter. In embodiments including an inner tube, the inner tube may extend the entire length of the catheter or only along a portion of the length of the catheter. The inner tube may be attached to the catheter using adhesive, sonic welding, or other techniques. Alternatively, the inner tube may be integrally formed with the primary catheter body, for example, via a molding or milling process. The catheter may include a forward facing port 320B. The forward facing port may be defined by a circular opening formed in a distal facing end wall of the catheter 304.

Although a helical slit is shown, the conduit 304 may alternatively or additionally have a port of other shape. Exemplary port shapes include a circular hole, a plurality of discrete holes arranged in a helical pattern around the conduit, a cage or mesh type opening, and the like. As shown in fig. 25E, the spiral slit port 320A may advantageously improve dispersion of fluid infused into the surrounding medium through the catheter 304.

The distal tip of the catheter 304 may have an atraumatic geometry. For example, the catheter may include a substantially spherical or bulb-shaped portion 322 at its distal end as shown. In embodiments where the conduit 304 includes a stepped down or reduced diameter portion, the conduit may include a radius or flange 324 to transition between the different diameters. For example, as shown in fig. 25C-25D, a tapered transition may be formed between a reduced distal portion of the catheter and an enlarged proximal portion of the catheter. The tapered transition may be conical. The tapered transition may be convexly or concavely curved.

The distal portion of the catheter 304 may be formed, coated or impregnated with a radiopaque, magnetic or other imageable material. For example, a separate inner tube in which the fluid port is formed may be formed of such materials and attached to the outer catheter body. The imageable material can facilitate visualization and guidance of the catheter tip under fluoroscopy or other imaging techniques (e.g., MRI, CT, PET, etc.).

The conduit 304 may be formed from any of a variety of materials. Exemplary materials include polyimide, PEEK, polyurethane, silicone, and combinations thereof.

Drug delivery system 300 may be used in a similar or identical manner to the drug delivery systems described above. Fig. 26 illustrates an exemplary method of using the system 300. As shown, the needle 302 may be inserted percutaneously into a patient in the lumbar region of the patient's spine, for example, using standard lumbar puncture techniques. The curved distal tip of the needle 302 may help guide the distal opening of the needle into the intrathecal space IS without damaging the spinal cord SC. The needle 302 may be inserted into the intrathecal space only to a small extent, for example, about 1cm from the intrathecal space. A catheter 304 may be inserted through the needle 302 to position the distal tip of the catheter within the intrathecal space. As mentioned above, in some embodiments, the catheter 304 protrudes from the needle 302 only a small amount, e.g., about 1 cm. The proximal end of the catheter 304 or needle 302 may be coupled to a pump system 310 for infusing or aspirating fluid through the catheter or needle. In some arrangements, the pump system includes separate drug and buffer channels, each with a respective pump. The pump system may be coupled to the dual lumen of the catheter, for example, at the bifurcated proximal portion of the catheter. In other arrangements, a first channel of the pump system may be coupled to the needle and a second channel of the pump system may be coupled to the catheter. In other arrangements, the conduit may be omitted, and the pump system may include a single channel coupled to the needle, or may include multiple channels coupled to the needle.

The controller 104 (e.g., a programmable computer processor) or a user may control the pump system 310 to infuse and/or aspirate fluid from a patient via a catheter and/or needle.

In an exemplary embodiment, the drug may be infused through a first fluid channel of the system 300, and thereafter, a supplemental agent may 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 adjunctive agents include drug-containing fluids, buffer fluids, artificial CSF, natural CSF previously aspirated from the patient, saline, and the like. In some embodiments, the supplemental agent can be CSF previously aspirated from the patient, and CSF can be aspirated and infused using the same syringe without withdrawing CSF from the syringe, thereby maintaining a closed sterile system.

Fig. 28A illustrates an exemplary drug delivery system 400 that may be used for intrathecal infusion and/or aspiration of fluids. The system 400 is substantially similar to the system 300 described above, but in the system 400, fluid is delivered directly to deliver suction through the needle 402 without inserting a catheter through the needle. Needle 402 may be coupled to pump system 410 at its proximal end. As in the systems described above, the pump system 410 may have multiple fluid channels (e.g., one channel for the drug and another channel for the supplemental agent). Pump system 410 may be connected to needle 402 by one or more fluid tubes. A hub may be formed on or coupled to the needle 402 to connect the needle to the fluid tube. For example, a Y-connector port may be used to connect the pump system 410 to the needle 402. Needle 402 may have various diameters and, in an exemplary embodiment, may be a 22 gauge needle. One or more valves 414 may be disposed in-line in the fluid tube, in the needle 402, or in the pump system 410. The valve 414 may be a one-way valve, a check valve, or the like.

The needle may have any of a variety of fluid ports formed therein. For example, as shown in fig. 28A-28B, the needle 402 may include a spiral slit fluid port 420A formed adjacent the distal tip of the needle. Fluid port 420A may be laser cut. As another example, as shown in fig. 29, the needle 402A can have a helical lumen 418 disposed adjacent to the distal fluid port 420B. The helical lumen 418 may facilitate turbulent flow of infusate through the distal fluid port to better disperse the fluid. The needle 402 may include a sharp pencil tip. As another example, as shown in fig. 30A-30C, the needle 402B can include an inflatable member 426, such as a balloon or septum, disposed in the distal tip of the needle. The needle 402 may include a sharp tip. The inflatable member 426 may be initially retracted within the tip of the needle 402, and the sharpened tip may be used to pierce the dura D or other tissue of the patient to facilitate needle insertion. Once the distal tip of the needle 402 is positioned in a desired location, such as within the intrathecal space, the inflatable member 426 may be deployed over the needle, as shown in fig. 30B. Deployment of the inflatable member 426 may be accomplished by infusing a fluid through the needle 402. The inflatable member 426 may include one or more fluid ports formed therein through which fluid may be infused or aspirated. For example, as shown in fig. 30C, the inflatable member 426 may include a helical fluid port 420A formed therein through which fluid may be infused. The inflatable member 426 may be formed of a soft material, such as 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 may be formed of a flexible biocompatible material, such as silicone.

In some embodiments, volumetric displacement of CSF may be used to move the infused drug through the intrathecal space of the patient. For example, fluid may be aspirated from the intrathecal space before, during, or after infusion of the drug to propel the drug in the intrathecal space in a desired direction. The fluid used for such volume replacement may range from about 1% to about 20% of the total CSF volume of the patient. The fluid may be aspirated from the patient and then subsequently reinfused.

The system disclosed herein may be used for patient-specific infusion. In an exemplary patient-specific infusion method, the CSF volume of a specific patient may be determined, for example, by calculation or estimation. For example, a pre-or intra-operative image of the patient may be captured. The images may be one or more MRI images of the patient's head and spine and/or the entire central nervous system. Image processing routines or manual estimation techniques, such as correlation with 3D anatomical models, may be used to calculate or estimate the total CSF volume of the patient. The calculated or estimated CSF volume may be used to adjust infusion and/or suction profiles for a particular patient. For example, about 1% to about 20% of the calculated or estimated total CSF volume may be aspirated from the patient prior to infusion of the drug to push the drug in a desired direction (e.g., cephalad or caudal within the intrathecal space of the patient).

In some embodiments, the method may include measuring the CSF head-to-body volume of the human using magnetic resonance imaging or other means. The method may comprise therapy or drug infusion performed by removing and/or infusing 0.5% to 20% of the total CSF volume of the patient. Methods may include therapy or drug infusion performed by removal and/or infusion of artificial CSF, buffer solution, or saline in conjunction with delivery or therapy of the drug. The method may include delivering the drug or therapy at a volumetric flow rate in a range of about 0.1ml/min to about 30 ml/min. The drug and additional volume (e.g., aspirated CSF, artificial CSF, buffer, etc.) may be delivered using pulsatile delivery as disclosed herein and/or infused using pulsatile delivery based on physiological parameters as disclosed herein. The drug and the additional volume may be infused serially or in parallel. Volume replacement and/or patient-specific drug or therapy infusion may advantageously provide better biodistribution of the infused drug.

Infusion flow rates for the systems disclosed herein may range from about 0.001ml/min to about 50 ml/min.

Spinal needle

In some embodiments, the delivery device may be or include a needle, such as a spinal needle. An exemplary spinal needle may be referred to herein as a "Pulsar Spinal Needle (SN)".

Fig. 31A-33 illustrate an exemplary pulser spinal needle 500. The body 501 of the needle 500 may have a gauge in the range of 7-40G. The needle 500 may be formed from a variety of materials, such as stainless steel, titanium, nitinol, rigid plastic, 3D printable materials and compounds, or combinations thereof. The needle 500 may include one or more tip outlets 502. The tip outlet 502 may be a standard outlet, a spiral outlet, a plurality of axial holes, a plurality of axial slits, or other shapes. The tip outlet 502 may be shaped to enhance dispersion of fluid exiting the needle. Instead of or in addition to the tip outlet 502, the needle 500 may have one or more outlet holes 504. The size, shape, including the circular and elliptical shapes shown, or location of the exit orifice 504 is such that a uniform axial infusion generates turbulence whose direction, momentum toward a distant target, combines with radial flow to distribute or "fill" around the axial flow. The needle 500 may include a needle hub 506. The needle manifold may include depth markings, markings to indicate the orientation of the tip outlet 502 or other outlet ports 504, or the like. Needle 500 may include a tube set 508, for example, for fluidly connecting with a proximal end 510 of needle 500. Tube set 508 may include a micro-lumen extrudate 512, for example, 0.005"to 0.1" inner diameter. The tube set 508 may include a low or zero dead volume luer 514 or other connector. Tube set 508 may include branches with ergonomic fittings to connect to multiple syringes, e.g., to be loaded into a syringe pump. In some embodiments, tube set 508 can accommodate 1-10 syringes. The bifurcation may include one or more valves, which may be configured to prevent or limit mixing of the fluid passages at the bifurcation. The exterior, e.g., outer surface or diameter, of the needle 500 may include a coating or other surface treatment, e.g., to prevent or reduce adhesion of the drug or other infusate to the needle 500. In some embodiments, the outer surface of the needle 500 may be coated with PTFE. Such a coating or treatment may reduce adhesion of the drug to the needle surface during infusion in the CSF, for example, to prevent removal of the drug with the needle 500 upon retraction of the device. The needle 500 may be formed as a multi-layer composite. For example, needle 500 may be a composite rigid needle having layers comprising one or more structural layers with a pattern of perforations alternating with layers of hydrophilic or nanoporous material to allow local penetration into CSF and contact with tissue in addition to the primary infusion flow. The needle 500 may be formed as a sandwich of structural layers (one or both outer surfaces having a perforation pattern) with a reservoir disposed between the outer layers. The reservoir may comprise a hydrophilic or nanoporous material therein. The needle 500 may include a hydrophilic or nanoporous layer. The hydrophilic or nanoporous layer may contain treatment material that is released upon contact with CSF, or the needle 500 may be soaked to absorb treatment material prior to device insertion. The needle 500 may include any of the features of the other spinal needles or delivery devices disclosed herein.

Fig. 31B shows an exemplary spinal needle 500. The illustrated spinal needle 500 may be referred to as spinal needle 1 or "SN 1". The needle 500 may comprise a blunt tip 51622 Ga needle with a total of 5 holes: two holes 502 axially aligned on one side and three additional holes 504 in rings spaced around the circumference of the needle 500. A pair of holes 502 may be inserted in "top" alignment to direct flow along the spinal axis within the dura mater. While the needle shown is effective for use in sheep models, other designs may require less effort and be less pliable, such as by blunting the tip. The needle 500 may include any of the features of the other spinal needles or delivery devices disclosed herein.

Fig. 32B shows another example spinal needle 500. The illustrated spinal needle 500 may be referred to as spinal needle 2 or "SN 2". Needle 500 may include a more pointed distal tip 518 than SN 1. The inner surface finish of the needle may be that of a commercial needle (used as a control needle). The fluid hole 502 of the needle 500 may be positioned closer to the distal tip 518 to minimize leakage and allow the hole 502 to be located inside the dura in small anatomical structures. This, in addition to the relatively small aperture 502 and radiation arrangement, may effectively minimize leakage. A pair of axially aligned holes 502 in SN1 may be replaced by axially extending slots 502' to further focus flow to the skull/brain. Alignment marks may be formed on the needle 500, for example, by laser marking to align with the slots. The probe lock alignment features may also be matched or aligned with the slot locations. The needle 500 may include any of the features of the other spinal needles or delivery devices disclosed herein.

Fig. 33 shows two additional example spinal needles 500. The needle shown at the top may be a dual lumen needle with a separate intermediate channel 520 opening at the tips 516, 518. The middle channel 520 may be surrounded by another channel 522 having a plurality of side outlets 504, e.g., 2-4, around the perimeter. The needle 500 shown at the bottom may be a three lumen needle with a separate medial channel 520 that opens at the tips 516, 518 and is surrounded by two additional separate channels 522 with longitudinally staggered side ports 504. The needle 500 may include any of the features of the other spinal needles or delivery devices disclosed herein.

Threadable/steerable catheter

In some embodiments, the delivery device may be or may include a catheter 600, e.g., a threadable and/or steerable catheter. The exemplary catheter 600 may be referred to herein as a "Pulsar wireable/steerable catheter (TC/SC)" or "Pulsar catheter".

Fig. 34 shows a comparison of performance between an exemplary pulser catheter and an exemplary pump system of the type described herein (which may be collectively referred to as a pulser catheter system) and a manual bolus injected with a commercially available catheter. As shown, material injected using the Pulsar catheter system has successfully spread into the cranial space as compared to the comparative catheter, where there is a rearward leak into the lumbar space.

Fig. 35 shows data from a preclinical study in which an exemplary Pulsar catheter is shown to provide targeted intrathecal therapy with overall biodistribution as compared to a manual bolus.

Fig. 36 and 37 show an implantable catheter 600 having an implantable port 602 and a pump 604 having a disposable injection fitting 606 for interfacing with the port 602. Catheter 600 may be a Pulsar catheter. Alternatively, a manual syringe or syringe 607 may be used. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 37 shows that the catheter 600 may be threaded by a removable guidewire 608 (first guidewire 608 with catheter 600 on) or may be threaded using a stylet (stylet pushing the catheter). A guide catheter may be used through the catheter 600 (the guide catheter may be passed first, then the flexible implantable catheter 600 may be passed through the guide catheter, and then the guide catheter may be removed). Catheter 600 may be passed with steering wire 612 (fig. 44) using built-in column strength members (e.g., wires, coils, braids, etc.) to navigate the spine or other anatomical structures. Catheter 600 is particularly useful in situations where spinal fixation or stabilization is to be applied to a patient, for example, using implanted bone anchors and rods. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

38A-38C illustrate an exemplary catheter 600, the catheter 600 may be a microcatheter, the OD of the body 601 of which is 0.030-0.15 ". As shown in FIG. 38A, the catheter 600 may include a plurality of lumens 614, e.g., 1-5. the catheter 600 may include radiopaque markers 616 for imaging, e.g., marker bands or markings. the markers 616 may be formed at a particular retracted length from the tip 618 and/or from the side ports or outlets 620. the material of the catheter lumen 614 may include Pellethane, fused silica, low density polyethylene (L DPE), silicone, Polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyamide, and/or combinations thereof. FIG. 38B illustrates a cross-sectional view of a multi-lumen catheter 600 having an internal core wire 622. FIG. 38C illustrates a layout of a three-lumen catheter 600 having various additional features. the catheter 600 may include PTFE or other coatings on the OD of the catheter 600 to minimize adhesion of drugs to the catheter surface other tissue during infusion of CSF, and may also include a drug adherent coating 626 to protect the catheter 600 when the catheter 600 is extended, or when the catheter 600 is coupled to a catheter 600, including a catheter 600, the catheter 600 may include a drug adherent coating 626 to minimize the drug adhering to the catheter 600, and may be removed from the catheter 600, and may include any other features disclosed herein as a catheter 600, a catheter 600 may include a catheter hub, a catheter 600.

Fig. 39A-39C illustrate an exemplary catheter 600. The catheter 600 may include a crescent or arcuate fluid passage or lumen 632 with a unique tip and staggered outlet configuration. For example, the catheter 600 may include two lumens 614, each having a distal outlet 634. The lumens 614 may have different lengths such that the distal outlets 634 are staggered along the length of the catheter 600. The catheter 600 may have a central lumen 614 coaxial with the outer lumen 614, or may include a central lumen 614 having up to four arcuate lumens 632. One or more of the lumens 614, 632 may include a manifold 636, and one of the lumens 614, 632 may have a core wire 622 extending therein. The arcuate lumen 632 may include radial or distal ports 620, 634. The catheter 600 may include a larger lumen 614 and two smaller lumens 614, one of which may be dedicated to the core wire 622. In another example, the catheter 600 may include side-by-side circular and crescent-shaped cavities 614, 632. In another example, the lumens 614 may be coaxial, one extending around the other. The catheter 600 may include side or distal ports 620, 634 and a marker 616. Catheter 600 may be a Pulsar catheter. The catheter may include any feature of the other catheters or delivery devices disclosed herein.

Fig. 40A-40C illustrate an exemplary catheter 600. The catheter may include outlets or fluid ports 634 that are staggered along the length of the catheter 600. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein. Fig. 40B illustrates that the outlet configuration can be customized for a particular patient, infusion, disease, etc. The position of the fluid ports 634 along the length of the catheter 600 may be adjusted in situ, for example, by longitudinally sliding one or more layers 614 of the catheter 600 relative to one or more other layers 614 of the catheter 600. FIG. 40C shows a multi-lumen catheter 600 having alternating outlet 634 and core wire 622.

41A-41C illustrate various catheter outlet/tip configurations. Fig. 41A shows a catheter 600 having a spiral or helical distribution of the outlets 634 of the three lumens 614, which may help maximize dispersion. One of the outlets 634 may have a relatively small diameter and an expanded conical configuration. Fig. 41B shows a catheter 600 with a staggered bifurcated tip design 638, which may help provide better biodistribution at the distal end 618 of the catheter 600. Catheter 600 may be inserted into the intrathecal space as a regular tip/staggered port catheter. Once the catheter end 638 is in its desired position, it may be bifurcated by rotating or otherwise actuating the control wire 640 from the proximal end 642. Fig. 41C shows a catheter 600 having a helical cut 644 extending around the tip 618. In an example, the stiffening coil 646 may extend around the tip 618 between the helical cuts 644. The tip 618 may be formed of polyimide or various other materials. Catheter 600 may be a Pulsar catheter. The catheter may include any feature of the other catheters or delivery devices disclosed herein.

Fig. 42 shows a single lumen catheter 600 having a smaller radial hole 620 at the proximal location and a larger hole 634 at the distal location or end 618. The smaller holes 620 may be spaced around the circumference of the conduit 600, for example, to surround the entire OD of the conduit 600. For example, the holes 620 may be arranged in axially aligned groups, in a ring around the circumference, or in angled or helical groups. The distal/tip opening 634 of the catheter 600 may effectively bias flow out of the tip 618 until backpressure forces flow out of the side hole 620. The side holes 620 may be smaller and/or have a smaller total cross-sectional area than the distal tip port 634. This configuration distributes the flow of therapeutic fluid through catheter 600 between side aperture 620 and distal aperture 634. For example, if the cross-sectional area of the side aperture 620 is equal to the cross-sectional area of the distal aperture 634, flow is evenly distributed between the side aperture 620 and the distal aperture 634. The relative sizes may be configured as desired, e.g., 30% -70%, 40% -60%, 50% -50%, 60% -40%, 70% -30%, etc. The catheter 600 may include a plurality of exit holes 620 of varying size along the length (e.g., small to large from proximal to distal) for infusion along the length or at a desired location. Catheter 600 may be a Pulsar catheter. The catheter may include any feature of the other catheters or delivery devices disclosed herein.

Fig. 43A shows a catheter 600 having a body 648, the body 648 having a substantially flat or curved cross-section. The catheter 600 may facilitate centering, easy pushability, less damage to the CSF space 650, and/or less problems with post-implant flexion. Further, catheter 600 may include core wire 622, for example, in sheath or lumen 650 on the concave side of body 648. The conduit 600 may alternatively have an i-beam configuration. The catheter 600 may include staggered outlets 634. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 43B-43F illustrate various features that may be included with the catheter 600 to increase turbulence to disperse the infused material 652 and/or to enhance circumferential diffusion of the infused fluid. For example, the catheter 600 may include a blind end channel 614 or block 653 having side outlets 620, 634. In this example, the infused material 652 impacts the blind end of the cavity 614 and exits the side outlets 620, 634 in a very turbulent manner. As another example, the catheter 600 may include a cage member 654 having a side outlet 620. As another example, the conduit 600 may include a cage member 656 having a 360 degree radial outlet 620. As another example, catheter 600 may include a spiral or helical cut 644 in side lumen 614 as an exit port to facilitate dispersion and infusion in an arc (e.g., a 270 degree arc that may provide the greatest divergence in some embodiments), and lumen 614 having exit port 634 at distal end 618. Catheter 600 may be a Pulsar catheter. The catheter may include any feature of the other catheters or delivery devices disclosed herein.

Fig. 44 illustrates catheter steering and/or navigation features. The catheter 600 may include a steerable wire 612 having a tip 658 that may be selectively angled or curved. The steerable wire 612 may be built into the catheter 600. The catheter 600 may include a curved stylet or guide wire 608 for navigating through the vertebral space during threading. The catheter 600 may include a task-specific lumen 614 extending from the tip 618 along a relatively short length of the catheter 600 to serve as a dedicated guidewire lumen. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Catheter 600 herein may include features that allow catheter 600 to "grow" or expand over time, for example, in connection with the growth of a patient in which the catheter is implanted. Fig. 45A shows a catheter 600 having features that expand with the patient over time as the patient grows. Catheter 600 may include an inner layer 660 incorporating a standard Pulsar catheter tip, a mixing design disclosed herein or other outlet configuration to allow for therapeutic infusion. Multiple lumens 614 may be incorporated. One or more lumens 614 may be used to run a stylet or guide wire configuration to allow for increased threading, deflection, and/or steering capabilities. The inner wire 608 may be preformed in any of a variety of advantageous shapes in accordance with the features described above. The catheter 600 may include another layer 662 overlapping the inner layer 660 or lumen. The catheter 600 may allow the two layers 660, 662 to move relative to each other to allow the overall length of the catheter 600 to increase as axial tension is applied. The outer layer 664 may cover the entire length of the catheter 600 to form a seal with the tip 618 and over the multiple layers 660, 662 that form the expandable portion of the catheter 600. The expansible portion of catheter 600 may be made of several layers that allow axial lengthening. Ports 620, 634 may be included at various locations along catheter 600 and in different layers to allow axial elongation. The outer sheath 664 may be pre-formed to its shortest length by bundling 664 the layers 666 to allow it to be sealed but expanded when pulled axially. The beam portion 666 may be aligned with the overlapping portion of the two layers 660, 662. The outer jacket 664 can be a polymer-based thin layer. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 45B shows a catheter 600 having a flexible core 668 with a multi-layer sheath design. The flexible core 668 may have a body or a portion thereof having a flexible or coiled configuration. The tip 618 may be bent using a flexible core 668. The catheter 600 may be pushed to deflect the rigid structure for steering and steerability. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 45C shows a catheter reinforcement layer 670 having a braided 672 and/or coiled 674 structure. The structures 672, 674 may improve the structural and steerable properties of the catheter 600. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 46 shows a catheter 600 having a balloon 676, for example, at the distal tip 618. The balloon 676 may be used to hold the catheter 600 in place. The balloon 676 may have a first expanded state 677 wherein the balloon 676 centers the catheter 600 within a lumen or cavity in which the catheter 600 is disposed and still allows fluid to flow through the balloon 676. For example, the balloon 676 may have wings 679, such as four as shown, that can be expanded to establish a diameter without obstructing the lumen or cavity. The balloon 676 may have a second expanded state 678 in which the balloon blocks a lumen or cavity in which the catheter 600 is disposed, which may be useful for selective infusion, for example. The balloon 676 may be inflated or expanded to enlarge the infusion perimeter along the catheter tip 618. This may be useful, for example, in neonates or other patients engorged in the intrathecal space without restriction to drug infusion. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 47 shows a needle 680 that may be used to insert a catheter. In some embodiments, catheter 600 may be inserted using a Touhy insertion needle.

Catheter 600 may include a tube set 682, for example, for fluidly connecting with proximal end 642 of catheter 600. Fig. 48A illustrates an exemplary tube set configuration. Tube set 682 may include a micro-lumen extrudate 684, for example, a 0.005"to 0.1" inner diameter. Tube set 682 may include a low or zero dead volume luer or other connector. The tube set 682 may include a branch 686 with ergonomic fittings to connect to a plurality of syringes 688 loaded into a syringe pump, for example. In some embodiments, tube set 682 can accommodate 1-10 syringes 688. The bifurcation 686 may be valve controlled.

Fig. 48B shows an exemplary extension wire for a single lumen needle or catheter.

Fig. 48C shows an exemplary extension wire of a three-lumen needle or catheter.

Fig. 49 shows a catheter 600 having a multi-layer structure. The catheter 600 may include a plurality of fluid chambers 614. The catheter 600 may include any one or more of (1) an inner liner 690, (2) a braided/rolled layer 692, and (3) a lubricious outer sleeve 694. Such a configuration may improve the threading and steering capabilities of catheter 600. The catheter body 601 may be formed from multiple segments with varying stiffness, flexibility, and/or column strength. The characteristics of each segment may be controlled by the catheter structure and/or the use of proprietary materials. Catheter 600 may be threaded using several methods, including (1) over guidewire 608, (2) using an obturator, and/or (3) only through catheter 600 itself. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 50 shows a multilayer composite conduit 600. The catheter 600 may include a structural layer 700 having a pattern of perforations 702 alternating with a layer 704 of hydrophilic or nanoporous material to allow local penetration into the CSF and contact with tissue in addition to the primary infusion flow. The perforations 702 may be any suitable shape, including parallelepiped, oval, arc, circular, and the like. The hydrophilic or nanoporous layer 704 may contain treatments that release the treatment when contacted with CSF under infusion pressure, or may soak the device to absorb the treatment material prior to insertion of the device. The catheter 600 may comprise a sandwich of structural layers 700 (one or both having a pattern of perforations 702) with a reservoir 706 disposed therebetween. The reservoir 706 may include a hydrophilic or nanoporous material therein. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 51 illustrates an implantable port 708 that may be used, for example, to fluidly or otherwise connect with a catheter 600 as described herein. The port 708 may include multiple septums 710 to connect to each lumen 614 independently, or one port or all ports. The port 708 may be used with a single-use syringe system. Port 708 may include an in-line bacterial filter. The port 708 may be configured to vibrate or otherwise move the catheter tip 618 to reduce the chance of occlusion. The port 708 may include a connector 712 having a plurality of individual channels 714 (e.g., 3 channels) and a needle 716. Alignment between the center alignment port 718 and the 0-ring 720 may ensure that the connector 712 is properly positioned. Once in place, the needle 716 may be deployed into the septum 710.

Fig. 52A-52B illustrate an exemplary implantable and expandable catheter 600 for compensating for patient growth. The length of the catheter 600 may be increased over time, either manually or automatically, to an extent commensurate with the patient's growth. The length of catheter 600 may be wrapped around multi (e.g., three) lumen port 722. During initial implantation, the surgeon may set an initial length (usable length) of catheter 600. As the patient grows, the port 722 may be rotated to deploy or release a portion of the catheter 600 to provide additional available catheter length.

An external actuator 724 may be used to rotate the port 722. The actuator 724 may be magnetic. The actuator 724 may be formed as an interlocking mechanism to allow the port 722 to be rotated precisely to the desired catheter length. The port 722 and actuator 724 may have predetermined locations or markings corresponding to desired units of length to expand the catheter. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

The catheter 600 disclosed herein may include an anchoring feature 726, for example, to prevent the catheter 600 from falling out after implantation. Fig. 53A shows a catheter 600 having a balloon 676 that can be inflated or expanded to anchor the catheter 600 and/or allow target occlusion for local infusion. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein. Fig. 53B shows a catheter 600 with an inflatable or expandable balloon 676 that can be used to close off intrathecal spaces or other areas/lumens. The balloon 676 may be placed distally, i.e., at the distal tip 618, or proximally, i.e., at the proximal end 642, to block flow in either direction. Only the distal balloon 676 may be inflated to control or restrict flow in the proximal direction. Only the proximal balloon 676 may be inflated to control or limit flow in the distal direction. The two balloons 676 can be inflated simultaneously to only control or restrict the flow between the balloons 676 or to maintain the therapeutic agent in a designated location. The plurality of ports 620, 634 may be used to administer a therapeutic agent distal to the distal balloon 676, proximal to the distal balloon 676, distal to the proximal balloon 676, proximal to the proximal balloon 676, or any combination thereof. More than one or two balloons 676 may be utilized in the same manner to control the location of flow, isolation, or therapeutic combinations thereof, for example, for as many therapeutic lumens as incorporated in catheter 600. The distal balloon 676 may be retracted into the lumen 614 of the catheter tip 618 when the balloon 676 is threaded, steered, introduced, or used at various times, which will facilitate delivery of the therapeutic agent. The proximal balloon 676 may be fixed in the wall 694 of the catheter 600 or may be located on an outer sheath that allows its position to be slid distally or proximally to position the balloon 676 for use. The balloon 676 may be positioned at various locations forward or rearward of the ports 620, 634 to activate or deactivate access to the defined ports 620, 634. The number of ports 620, 634 may be as many as all of the lumens 614 required or defined by the catheter 600 to deliver the therapeutic agent. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 54 shows a catheter 600 having deployable features for anchoring the catheter 600 or its tip 618. The feature 726 may be deployed to anchor the catheter 600 at the tip 618 or other location along the length of the catheter 600. The preformed nitinol or shape memory wire 728 may be retracted into the lumen 614 of the catheter 600 during insertion, threading, or other desired steps of the acute procedure. Once it is desired to anchor the catheter 600, the nitinol wire 728 may be extended to assume its preformed shape and anchor the catheter 600 with the outwardly extending portion 730. The nitinol wire 728 may be a single wire of many different shapes beneficial for having the desired anchoring effect, or a double wire for increasing its expandable range in two or more directions. The anchoring feature 726 may be used multiple times along the length of the catheter 600 to increase its anchoring effect. The nitinol wire 728 may be shaped atraumatic and may have different diameters to achieve optimal characteristics of flexibility and stiffness. The preformed wire 728 may have a number of different bends therein and in different directions. The nitinol wire 728 may also be used for flexibility, steerability, or a location to change the bending or stiffness of the catheter 600 for the benefit or characteristic of placement or threading. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 55 shows a catheter 600 similar to that shown in fig. 54. The nitinol or shape memory wire 728 may be formed in the shape of a rotation/helix 732 or a bottle opener 734 to anchor it into tissue in a circular motion. The wire 728 may be deployed along the length of the catheter 600 at or proximal to the distal tip 618. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 56 shows a catheter 600 having an anchoring feature 726 extending therefrom. The anchoring features 726 may include hairs or mandrels 736 extending from the catheter to anchor the catheter to the dura when threaded. If sufficient axial force is provided, the mandrel may be flexible enough to remove the catheter. The catheter may be a Pulsar catheter. The catheter may include any feature of the other catheters or delivery devices disclosed herein.

Fig. 57 shows a catheter 600 with anchoring features 726 in the form of sutures 738, protrusions 740, or anchors. The anchoring feature 726 may be deployed from the catheter 600 to anchor it in place, for example, on the dura 742. This may prevent or limit migration, for example, allowing the catheter 600 to remain in place as the patient moves. Since catheter 600 is anchored, as the patient increases in height, distal end 618 of catheter 600 moves, and the extra length of catheter 600 can be coiled and pulled out. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 58 illustrates a catheter 600, the catheter 600 configured to expand to account for patient growth. The catheter 600 may include a retractable distal anchor clip, splines, and/or hooks. Catheter 600 may be selectively expanded by stretching helically cut portion 744 of body 601. The catheter may include a magnetic "anchor" device. The anchor may be under or on the skin of the patient, for example in the form of a port on the device. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 59 shows a catheter 600 with features for real-time 3D mapping or catheter localization. For example, the conduit 600 may include a passive electrode ring 746 wired to a junction box for the mapping system. The map may be generated from an MRI, catheter scan, or other accessory. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 60 illustrates a catheter 600 and associated method of blanket infusion, wherein the catheter 600 is retracted upon infusion. Specifically, a first step may be used to infuse the cervical/brain (intracranial), then a second step may include radial infusion, with the catheter 600 retracted from the space for intrathecal "blanket" infusion. For example, the catheter 600 may be configured with a central lumen 614 having an outlet 634 at the distal tip 618, and arcuate lumens 632 may be distributed around the central lumen 614. Each arcuate lumen 632 may include one or more radial ports 620, 634. Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Fig. 61 and 61A show a catheter 600 with an extendable anchoring guide wire 608 for single infusion or long-term use. The guidewire 608 may include an extension 748 having an outwardly extending shape (e.g., a spiral shape as shown) to anchor the guidewire 608 with minimal flow resistance or anatomical trauma. The catheter may be a Pulsar catheter. The catheter may include any feature of the other catheters or delivery devices disclosed herein.

Fig. 61B shows a catheter 600 and anchor guide ("guide wire") system 750 including a guide 752 with anchors 752, in some embodiments, the system 750 may help ensure that an ideal catheter tip 618 is positioned for infusion, e.g., closest to the brain, with minimal obstruction to infusion flow, while leaving all infusion lumens 614, ports 634, 620, etc. for infusion without increasing the catheter diameter, the guide 752 and catheter 600 may be implanted for long-term infusion, may be introduced for a single procedure, or the guide 752 may be left implanted for multiple effective catheter replacements/introductions for infusion therapy, the guide 752 and the anchor 754 may be placed by using an appropriate microcatheter, the anchor 754 may be in the form of a helix to create an open infusion space by "pulling" hard meninges "away from the spinal cord to enhance the brain tip infusion, the entire guide/anchor 754 or a portion thereof may have a surface coating for functional compliance, lubricity, handling, and implant retention features for a special guide catheter/anchor infusion lead 752, or a portion thereof may have a mechanical retention feature for a flexible wire to be extended to a length that a flexible guide catheter 600, a flexible guide catheter or a flexible wire guide catheter may be used to adjust the length of a catheter 600, a flexible guide catheter extension guide, a flexible guide catheter or a flexible guide catheter may be used to include a flexible guide wire or a flexible guide catheter extension guide catheter 26, a flexible guide catheter or a flexible wire to a flexible guide catheter extension guide catheter 26 guide, a flexible guide catheter 26 guide catheter or a flexible wire to be used in a flexible guide catheter or a flexible guide catheter extension guide catheter 26 guide catheter or a flexible guide catheter extension to prevent extension or a flexible guide catheter extension to prevent extension or a flexible guide catheter extension to prevent extension to a length when a catheter extension or a catheter extension guide catheter extension or a catheter extension when a catheter extension guide catheter or a catheter extension to a catheter or a catheter extension when a catheter extension to a catheter length is used in a catheter or a catheter extension to a catheter length when a catheter extension to a catheter length is used to a catheter length, including a catheter length when a catheter length is used.

Multi-port intrathecal catheter designs have been described in the literature and continue to evolve due to their design advantages in infusion coverage and scope. In addition to the catheter tip, some uses of catheter designs with ports located along the catheter rely on flow outside the catheter in the intrathecal space. The catheter shown in fig. 62B-62C can potentially improve the performance of a multi-port, wireable intrathecal catheter, particularly when used in narrow anatomical structures. In a recent sheep study using a threadable catheter, it was observed that the anatomy (subarachnoid space) could be small enough that the catheter could come into contact with the spinal cord and dura mater, which could essentially elastically seal the catheter length and form a tent, leaving only two small triangular gap openings in the subarachnoid space for axial infusion. This essentially isolates each port injection to some extent. Fig. 62A schematically illustrates this "constrained catheter infusion" phenomenon, which is adapted from fluoroscopic infusion study observations.

In this case, a 0.042"OD smooth round crescent lumen multi-lumen squeeze tube catheter was used in sheep, and the whole milk solution was injected into the lumen of the sheath and compared to normal saline" chaser ". For one fluorescence map there are thin high contrast lines on one side of the device (due to the superposition effect of the contrast agent flow superposition lines), while a wider lower contrast flow image is produced from the fluorescence 90 degree angle of the map.

Fig. 62B shows an exemplary "grooved" catheter 600 with a surface design to minimize contact surface constraint of the infusion flow. The catheter 600 may include longitudinal channels 760 on the exposed surface 762 of the catheter 600 to create flow channels despite tissue contact to facilitate infusion flow along the catheter 600 even when in contact with elastic dura mater, spinal cord, or other anatomical structures. The conduit 600 may be formed by extrusion. The conduit may have closely disposed relatively tall radial ribs 764 or splines. The spaces between these protrusions 764 may form flow channels 760. The spacing of these features can be kept low to prevent tissue sagging, clogging, or entering the channel.

The conduit 600 may be splined or grooved along some or all of the length of the conduit. The illustrated arrangement shows splines 764 on the exposed "staggered" length of the catheter shaft, e.g., the length of the catheter along which the multiple ports 620, 634 are longitudinally spaced. The actual dimensions and proportions may be altered to balance various design requirements, including flow channel capacity and tissue span of the channel 760. Narrow, relatively deep channels 760 may be advantageous because they may remain open and the number of channels 760 may be relatively high. The spline extrusion ID may be a lumen 614 for a tip port 634, which may also serve as an over-the-wire guidewire lumen. The splined tube may be exposed within the staggered length (tip port 634 to flank port 620). The splined tube may be nested within the proximal outer tube 766. The spline channel 760 may also serve as an interleaved port lumen. A second outer tube 766 having a smooth inner and/or outer surface may be attached to or cover the spline tube. As shown in fig. 62C, the open end of the outer tube 766 may be referred to as an "interlace port". Catheter 600 may be a Pulsar catheter. Catheter 600 may include any of the features of the other catheters or delivery devices disclosed herein.

Additional features

Any of a variety of other features may be included or incorporated into the delivery devices disclosed herein, including various catheters and needles. The device may include a sensor that may be connected to the pump or an external device. Pressure sensors may be used to measure CSF pressure, e.g., calibrate the pump for CSF pulsatility, and/or to measure maximum CSF pressure during infusion for safety. Other sensors may be used to measure drug concentration, biomarkers, and the like. The apparatus may include a miniature camera and a light source.

The devices disclosed herein may be used in any of a variety of ways. In some embodiments, a convection-dispersion approach may be used, where the drug is followed by saline, or the patient's own aspirated CSF, or an artificial CSF, or a drug buffer, or another biocompatible fluid, to convectively displace and disperse the drug and enhance biodistribution in the CSF space (including the skull).

In some embodiments, alternating small pulse infusions of the drug and another fluid may be used. This may include aspiration of CSF followed by pulsatile/continuous infusion of drugs and other fluids.

In some embodiments, a small amount of another fluid may be infused first, followed by the drug.

In some embodiments, a small amount of another fluid, then a drug, then another fluid may be infused.

In some embodiments, a small amount of another fluid may be infused, followed by infusion of the drug and the other fluid in alternating pulses.

Following infusion, the CSF space may be pulsed (by withdrawing and infusing CSF, e.g., 0.1-1m L CSF, net 0m L) to create micro-beats in the CSF space to enhance tissue interstitial space and other small space drug absorption.

Many methods are particularly useful for a wearable catheter, including any one or more of the following: (i) simultaneously aspirating and infusing CSF from the distal tip and infusing drug from the staggered outlet to enhance drug distribution in the intrathecal space; (ii) infusing a drug and another fluid from the distal tip to push into the inner cytoplasmic reticulum and cranial cavity; (iii) infusing a drug from the distal tip and another fluid from the staggered outlet; (iv) aspirate CSF from the tip prior to any infusion; (v) aspirating CSF from the tip port while infusing from one or a sequence of staggered outlets to deliver medication to the tip, stopping the aspiration at a specified volume of infusion to prevent aspiration of medication, continuing the infusion from the staggered ports and/or the distal port at or near the tip; (vi) infusing a fluid compatible with CSF within a safe range prior to infusion in any of these methods to create space for accelerated infusion flow; (vii) after infusion, aspirate from Touhy needle to normalize ICP/CSF pressure; (viii) infusing the drug from one outlet and drawing CSF from the other staggered outlet to convect the drug to the staggered outlet; (ix) recirculating the drug between the interleaved ports to maintain local drug distribution between the ports; and (x) infusion, aspiration between Tuohy outlet and catheter outlet, including synchronized tip aspiration/(needle) infusion.

The system herein may be connected to a sensor or vest worn by the patient, where the vest may be compressed/decompressed periodically with pulsatile infusion to enhance diffusion of the drug in the CSF space.

The system herein may be connected to a light guide that switches colors to light to indicate patient breathing, and may time infusion pulses to the light to control and enhance diffusion.

Preparation methods for the systems herein may include pre-washing the lumen with saline, buffer, CSF, artificial CSF, HAS, or other fluids to prevent drug particle adhesion.

Preparation methods for the systems herein may include pre-filling and soaking the lumen with a drug to coat the lumen to prevent additional drug particles from adhering.

The system herein may allow for the introduction and infusion of in-line air in a controlled manner at the end of the infusion to minimize the dead volume of the drug.

The systems herein may include an implantable catheter and/or a pump. The catheter may be a valved catheter of the type described herein. The pump may be a constant flow or microdose programmable implantable, programmable and refillable (optional) pump. The catheter may include a flow and/or pressure sensor at the distal end of the catheter to detect displacement and/or occlusion of the catheter. The pump may be an implantable chamber pump having dual or single reservoirs (one reservoir containing a drug and one containing another fluid such as artificial CSF or drug buffer) attached to a catheter. Infusion through a catheter may include (i) a slow continuous succession through one lumen/outlet, multiple lumens/outlets, or the same lumen/multiple outlets of staggered size; (ii) pulsatile infusion; (iii) continuous infusion of drug and drug buffer; and/or (iv) infusion/aspiration to create pulsatility and perform a net positive infusion.

The systems herein can be used to pulse the CSF space (by withdrawing and infusing a small volume) to create micro-pulsation in the CSF space, thereby enhancing the absorption of interstitial and other small space drugs.

The system herein may include an implanted pump connected (via wireless architecture or otherwise) to a computer to monitor real-time drug infusion/pressure data. A drop in infusion rate, an increase in pressure, or other detected parameter may trigger an alarm that is sent to a caregiver or user.

The systems and methods herein may be used to treat any of a variety of conditions or diseases, including parkinson ' S disease, fibular-lie ataxia, canavan ' S disease, amyotrophic lateral sclerosis (a L S), congenital seizures, epilepsy (Drevets) syndrome, pain, Spinal Muscular Atrophy (SMA), tauopathy (Tauopathies), huntington ' S disease, brain/spine/Central Nervous System (CNS) tumors, inflammation, hunter syndrome (Hunters), alzheimer ' S disease, hydrocephalus (treatment of hydrocephalus), sanfilippo syndrome (sanfilippo) type a, sanfilippo syndrome type B, epilepsy, pre-epileptic vision, primary central nervous system lymphoma (PCNS L), Primary Progressive Multiple Sclerosis (PPMS), acute diffuse encephalomyelitis, prescription of motor fluctuation in patients with advanced parkinson ' S disease (Rx of motor fluctuation in motor syndrome, seizure syndrome ' S syndrome ', acute diffuse encephalomyelitis, acute repetitive state, or seizure replacement therapy, epilepsy, or neoplasms epilepsy.

The systems and methods herein may be used to deliver any of a variety of drugs, including antisense oligonucleotides, adenoviruses, gene therapy (adeno-associated virus (AAV) and non-adeno-associated virus (AAV)), including gene editing and gene conversion, oncolytic immunotherapy, monoclonal and polyclonal antibodies, stereopure nucleic acids, small molecules, methotrexate, edarone (ediavarone-conjugate), conotoxin, morphine, prednisolone sodium hemisuccinate, carbidopa/levodopa, tetrabenazine, Benzodiazepines (BZD) (diazepam and midazolam), alphaxalone or other derivatives, cyclophosphamide, idum (elapsin), iduronidase (aldosterone), topotecan, and/or busulfan (Buslfan).

Automatic injection pump

The systems herein can provide a customized drug delivery platform to address the unmet need for intrathecal and extravaginal delivery of drugs. This is particularly useful for the CNS, since the presence of the Blood Brain Barrier (BBB) is a major obstacle to drug delivery to the Central Nervous System (CNS). The most practical way to deliver drugs to the CNS by circumventing the BBB is through the intrathecal space. However, current manual intrathecal delivery techniques are not optimal and are not suitable for the delivery of therapeutic agents. The systems herein can provide improved controlled and repeatable biodistribution and diffusion of therapeutic agents in the CNS space. An exemplary system may include a programmable multi-syringe pump with a customized algorithm that may provide controlled intrathecal delivery of therapeutic agents.

An exemplary system may include any one or more of the following features:

driving and operating conditions: (i) three-drive system injection pump with independent control; (ii) each driver may communicate with each other; (iii) each injector can be independently operated through an independent push block; each drive may be programmed, for example, using a laptop computer or other computer system via RS-232 or other connection.

The pump function: programming each driver to have infusion/withdrawal functionality in a programmed sequence, such as (i) bolus mode; (ii) a pulsatile mode, (iii) a ramp-up mode, (iv) a variable flow mode; (v) a target volume; (vi) a target time; (vii) functional variables such as flow, volume, change in number of cycles, change in time delay between cycles, cycles synchronized with pressure sensor input.

Software: integrated programmable software for (i) programming the pump display and operating parameters and steps in an external computer system or portable computer; (ii) communication between multiple (e.g., three) drives; (iii) the ability to interact with an online pressure sensor.

A clamping system: the pump may include an automatic clamping system to clamp the tubing set at a predetermined time. The clamping system can clamp and release a plurality of extension lines. The clamping system can clamp according to infusion curve setting or a separate program. The clamping system may include clearly identified ports for the lumen and extension wires.

A sensor: the pump may communicate with a built-in/in-line sensor, such as a pressure sensor, 1CP sensor, etc.

Non-volatile memory: settings, medication dose profiles, syringe profiles (including custom inputs), acceptable force limits for different syringe types, and/or various other data may be stored in the system, including on non-volatile memory.

And (4) alarming: the system may provide an audible, visual, tactile or other alert based on flow, pressure, air bubbles, syringe empty, scram, ICP pressure high, online pressure high, etc.

Ergonomics: the system may have a compact design, be portable, have smooth edges and features, and customized illustrations and colors.

The drive of the pump system may have one or more of the following specifications:

the running precision of the pump is as follows: plus or minus 0.25 percent

Flow rate accuracy of the pump: plus or minus 2 percent

Reproducibility: plus or minus 0.05 percent

Syringe compatibility: 250 μ l to 50ml

Minimum flow rate: 1 mul/min

Maximum flow rate: 100ml/min

A display: is that

Non-volatile memory: is (store all settings)

A connector: USB; RS-485; RS-232

Linear force (maximum 100% force): 75 pounds (Adjustable power)

A driver motor: 0.9 degree stepper motor control (equivalent to 400 steps/revolution) or 1.8 degree stepper motor control (equivalent to 200 steps/revolution).

And (3) motor drive control: microprocessor with 1/32 microstepping or 1/16 microstepping

Minimum ram movement speed: about 0.24mm/min (assuming a scale length of 250. mu.l syringe 60mm, 50ml syringe 81mm)

Maximum ram travel speed: about 51mm/min (assuming a scale length of 250 μ l syringe 60mm, 50ml syringe 81mm)

AC/DC adapter: standard of merit

Stall detection: two independent stall detections

Pump system

The systems herein may include a pump system. The pump system may be configured to hold 1-10 injectable drug vials or syringes, each operating independently on a separate drive or through a synchronized drive. The pump system may use separate syringes or use the same syringe for CSF suction and infusion. The infusion profile may be customized manually or remotely according to a clinical infusion protocol. The scope of remote control (cable manual module or local wireless) functions may include start/stop, monitoring or program/parameter settings. Infusion/aspiration procedures/profiles may be pre-planned, stored on the media for reference or use. The pump may incorporate patient or environmental monitoring parameters for integration for display, feedback, and/or as data for algorithmic input for infusion/aspiration control.

The system may include customizable software with programmable manuals or through secure cloud algorithms for infusion/aspiration according to a drug regimen. The system can be programmed to increase the concentration of the drug to the target of interest (TOI) as needed. The software may be configured to infuse and aspirate simultaneously at the same or varying flow rates. The software can selectively, simultaneously or sequentially infuse/aspirate the syringe from various device port locations. The software may select volumes, flows, aspirations and infusions, infusion/aspiration profiles for different modes, such as constant rate infusion, pulsatile infusion, step-ramp-up infusion, aspiration timing and infusion delay, etc.

Medication infusion protocol data may be input into the pump system. Data may be entered manually or remotely (e.g., through a secure cloud), a USB may be preprogrammed, data may be entered from some other type of hard drive/hard wire, data may be downloaded from a cloud, etc.

The system may include a breath per minute (RPM) input, a respiratory diaphragm motion input, electrical input to the patient's ECG, respiration, CSF pressure, arterial/venous pressure, or other physiological parameters.

The system may be connected to one or more wearable sensors placed or worn by the patient, for example in an article of clothing (e.g., a vest), where the sensors or vest can be compressed/decompressed timed with pulsatile infusion to enhance diffusion of drugs in the CSF space.

The system may be connected to a light guide that can switch colors to light the patient to breathe, and can time infusion pulses to the light to control maximum diffusion.

The system may connect to an online pressure measurement system over time during a prescribed infusion and analyze the pressure data to indicate an emergency stop of the pump.

The system may include wireless connection functionality with computers and sensors to monitor different conditions of the patient. The system may be configured to provide automatic delivery of the secondary infusion when necessary or desired. The system can be configured with remote calibration capability to achieve dose accuracy. The dose data may be sent to ancillary computing software to monitor the infusion curve versus delivered dose in real time to ensure dose accuracy. The system may be configured so that pump infusion data may be accessed from any computer at any time to access patient infusion information and pump data management. The system may include an automatic priming feature that detects and eliminates air in the line. The priming bottle can be selected individually and the pump can prime the connected lines with fluid in the bottle until there is no air in the system. The system may be configured to introduce and inject in-line air in a controlled manner at the end of infusion to minimize drug dead volume.

A drug delivery system is disclosed that includes a catheter having at least one fluid lumen; a pump configured to infuse a fluid through a catheter; a sensor configured to measure a physiological parameter of a patient; and a controller that controls the pump to coordinate infusion of the drug through the catheter with the physiological parameter measured by the sensor.

The system may include one or more of: the controller synchronizes the infusion frequency with the patient's natural intrathecal pulsation frequency measured by the sensor; the controller synchronizes the infusion phase with the patient's natural intrathecal pulsation phase measured by the sensor; the controller establishes a sinusoidal approximation of the patient's natural intrathecal pulsation as measured by the sensor and synchronizes the infusion with the rising wave of the sinusoidal approximation; the controller establishes a sinusoidal approximation of the patient's natural intrathecal pulsation as measured by the sensor and synchronizes the infusion with the falling wave of the sinusoidal approximation; the sensor is configured to measure intrathecal pressure; the sensor comprises a first sensor configured to measure intrathecal pressure and a second sensor configured to measure heart rate, and the controller is 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 the infusion of the drug through the catheter with intrathecal pulsation of the patient based on the output of the second sensor; further comprising an implantable infusion port in fluid communication with the catheter and an extracorporeal syringe configured to mate with the infusion port; the catheter includes first and second fluid lumens, and wherein the controller is 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; or the sensor is 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 intraluminal pressure.

Disclosed are methods of delivering a drug to a patient, comprising inserting a catheter into an intrathecal space of a patient; measuring a physiological parameter of a patient using a sensor; and controlling the pump with the controller to coordinate the infusion of the drug through the catheter with the physiological parameter measured by the sensor.

The method may include one or more of: synchronizing the infusion frequency with the patient's natural intrathecal pulsation frequency as measured by the sensor; synchronizing the infusion phase with the patient's natural intrathecal pulsation phase measured by the sensor; establishing a sine approximate value of the patient natural intrathecal pulsation measured by a sensor, and synchronizing the infusion with the rising wave of the sine approximate value; establishing a sine approximate value of the patient natural intrathecal pulsation measured by a sensor, and synchronizing infusion with a descending wave of the sine approximate value; the sensor is configured to measure intrathecal pressure; the sensor comprises a first sensor configured to measure intrathecal pressure and a second sensor configured to measure heart rate; establishing a correlation between heart rate and intrathecal pressure based on the outputs of the first and second sensors when no infusion is taking place, and coordinating the infusion of the drug through the catheter with intrathecal pulsation of the patient based on the output of the second sensor; the catheter comprises first and second fluid lumens, and wherein the method comprises 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 is 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 intraperitoneal pressure; inserting a catheter such that it extends along a spinal cord of a patient, wherein at least a portion of the catheter is disposed in a cervical region of the patient's spine and at least a portion of the catheter is disposed in a lumbar region of the patient's spine; delivering a plurality of different drugs through the catheter, each drug being delivered through a respective fluid lumen of the catheter; controlling, with a controller, a pump to draw fluid through a conduit; the catheter comprises a plurality of outlets spaced apart in a craniocaudal direction along the length of the catheter, and wherein the method comprises infusing a drug through a first port of the catheter and aspirating fluid through a second port of the catheter, the second port being the head of the first port; infusing a medication through a port of a catheter disposed in a cervical region of a spine of a patient to push the infused medication into a cranial cavity; aspirating a volume of CSF from a patient; infusing a drug through a first proximal port of the catheter while drawing CSF through a second distal port of the catheter to form a drug bolus between the first and second ports; infusing previously extracted CSF at a location proximal to a bolus to propel the bolus in a distal direction; the volume of CSF aspirated from the patient represents about 10% of the total CSF volume of the patient; inserting a catheter through a percutaneous lumbar puncture of a patient; the infusing comprising 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 is delivered to a target region, the target region being at least one of an intrathecal space of the patient, a sub-vertebral 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 comprises at least one of antisense oligonucleotide, stereopure nucleic acid, virus, adeno-associated virus (AAV), non-viral gene therapy, exosome and liposome; the method comprises at least one of: gene therapy by drug delivery; gene editing by drug delivery; gene conversion by drug delivery; and non-viral gene therapy by drug delivery; the total CSF volume of the patient is determined and the infusion is adjusted according to the total CSF volume.

Disclosed are methods of delivering a drug to a patient, comprising inserting a catheter into an intrathecal space of a patient; controlling the pump with the controller to infuse the drug through the catheter; controlling the pump with the controller to draw fluid through the conduit; and controlling the infusion and the aspiration to target the drug to a target site within the patient.

The method may include one or more of: the infusion takes precedence over the patient's natural CSF pulsations to push the drug to the target site; the infusion is coordinated with the patient's natural CSF pulsation to push the drug to the target site; the infusion comprises delivering a bolus of the drug, followed by pulsatile delivery of fluid behind the bolus to propel the bolus towards the target site; the fluid comprises at least one of a drug, a buffer solution, and CSF aspirated from a patient through a catheter; at least a portion of the catheter is disposed in the target region; at least one of infusion and aspiration are coordinated with a physiological parameter of the patient; the physiological parameter is at least one of heart rate, intrathecal pressure, intrathecal pulsation rate, respiratory rate, lung capacity, chest expansion, chest contraction, intrathoracic pressure and intraperitoneal pressure; the catheter comprises first and second fluid chambers, and wherein the method comprises controlling the pump to alternately draw fluid through the first fluid chamber and infuse fluid through the second fluid chamber; inserting a catheter such that it extends along a spinal cord of a patient, wherein at least a portion of the catheter is disposed in a cervical region of the patient's spine and at least a portion of the catheter is disposed in a lumbar region of the patient's spine; aspirating a volume of CSF from the patient, infusing a drug through a first proximal port of the catheter while simultaneously aspirating CSF through a second distal port of the catheter to form a bolus of the drug between the first port and the second port, and infusing the previously extracted CSF at a location proximal to the bolus to urge the bolus in a distal direction; 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 is at least one of an intrathecal space of the patient, a sub-vertebral 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 comprises at least one of antisense oligonucleotides, stereopure nucleic acids, viruses, adeno-associated viruses (AAV), non-viral gene therapy, exosomes, and liposomes; at least one of gene therapy by delivering a drug, gene editing by delivering a drug, gene conversion by delivering a drug, and non-viral gene therapy by delivering a drug; the total CSF volume of the patient is determined and the infusion and/or suction is adjusted according to the total CSF volume.

A drug delivery catheter is disclosed that includes a tip having a first fluid lumen extending to a first fluid port, a second fluid lumen extending to a second fluid port, and a guidewire lumen; a pipe collector; and a body having a first fluid tube defining a first fluid lumen in fluid communication with the first fluid lumen of the tip, a second fluid tube defining a second fluid lumen 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 defining at least one internal passage in which the guidewire and the first and second fluid tubes are disposed, wherein the sheath extends from the distal end of the hub to the proximal end of the tip.

The apparatus may comprise one or more of: the tip has a tapered distal end; the first and second fluid ports are offset from a central longitudinal axis of the tip; at least one of the first and second fluid ports is aligned perpendicular to or at an oblique angle relative to the central longitudinal axis of the tip; the first and second fluid tubes extend uninterrupted through the header; the first and second fluid tubes terminate within the header at respective connectors to which the proximal extension tube may be selectively coupled; the guide wire extends uninterruptedly through the header; the first and second fluid tubes having respective fluid connectors at their proximal ends; at least one of the first and second fluid tubes is formed of fused silica; at least one of the first and second fluid tubes is coated in the shrink tube; the sheath is formed of polyurethane; the sheath includes an opening formed therein in fluid communication with the fluid port of at least one of the first and second fluid tubes; at least one of the first and second ports has a helical interior; at least one of the first and second ports has an interior that tapers toward the distal end of the port; the first fluid port is adjacent to the second fluid port; an auger rotatably mounted within the conduit; a piezoelectric transducer disposed within the conduit.

Disclosed is a percutaneous needle device comprising an elongate shaft defining at least one lumen therein; a sensor disposed at a distal tip of the elongate shaft; a display mounted to the elongated shaft configured to display an output of the sensor; and a connector disposed at a proximal end of the elongate shaft for making fluid connection with the at least one lumen.

The device may include a fluid reservoir and a flush dome in fluid communication with the lumen of the needle, wherein actuation of the flush dome effectively pumps fluid from the reservoir through the lumen of the needle.

Catheters are disclosed that include an elongate body having one or more fluid lumens formed therein; and a fluid port formed in the conduit, the fluid port being defined by a helical slit formed in a wall of the conduit.

The catheter may include one or more of: an atraumatic distal tip formed from a substantially spherical ball; the catheter includes a second distal-facing fluid port; a helical slit formed in a sidewall of the reduced diameter portion of the conduit; the conduit includes a tapered transition between the main body of the conduit and the reduced diameter portion of the conduit.

Disclosed are patient-specific infusion methods comprising 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 the drug into the intrathecal space of the patient.

The method may include one or more of: after infusing the drug, infusing the aspirated CSF of the patient to propel the drug in a desired direction within the intrathecal space; the total CSF volume is determined from preoperative images of the patient's central nervous system; the aspirated volume of CSF is in the range of about 1% to about 20% of the patient's total CSF volume; the drug is infused while the CSF volume is aspirated.

A drug delivery system is disclosed comprising an intrathecal catheter or needle having at least one fluid lumen; a pump configured to infuse fluid through the catheter according to a programmed infusion curve. The pump may comprise a plurality of syringes.

A method is disclosed that includes inserting a catheter into an intrathecal space of a patient, the catheter configured to increase in length as the patient grows.

The method may include one or more of: the excess lumen of the catheter is first implanted into the port and, as the patient grows, the catheter can be manipulated to extend its length as the patient grows; or a distal anchoring mechanism such that the axial tension of the catheter increases as the patient grows.

Methods of applying targeted infusion to the lumbar, thoracic and cervical regions of the spine and brain are disclosed. Methods may include using infusion curves and mechanisms targeting specific regions of the intrathecal space to assist in targeting

A method of anchoring a catheter within a patient's spine to avoid migration of the catheter upon implantation is disclosed.

A method of easily implanting a catheter from a lumbar region to a cervical region of a patient is disclosed. The method may include configuring the catheter for such easy implantation.

Needles configured to maximize dispersion during injection are disclosed. The needle may include multiple lumens to allow for simultaneous or independent infusion of the drug and buffer.

Us provisional application No. 62/159,552 filed on 11/5/2015; U.S. provisional application No. 62/239,875 filed on 10/2015; united states provisional application No. 62/303,403 filed on 3,4, 2016; united states application No. 15/151,585 filed on 5, 11/2016; and us application No. 15/662,416 filed on 28/7/2017; all hereby incorporated by reference in their entirety.

While the invention has been described with reference to specific embodiments, it should be understood that numerous changes could 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.