U.S. patent application number 16/877065 was filed with the patent office on 2020-09-03 for drug delivery systems and methods.
The applicant listed for this patent is ALCYONE LIFESCIENCES, INC.. Invention is credited to PJ Anand, Ayesha Arzumand, Morgan Brophy, Greg Eberl, Stela Moura, Deep Arjun Singh.
Application Number | 20200275948 16/877065 |
Document ID | / |
Family ID | 1000004838406 |
Filed Date | 2020-09-03 |
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United States Patent
Application |
20200275948 |
Kind Code |
A1 |
Anand; PJ ; et al. |
September 3, 2020 |
DRUG DELIVERY SYSTEMS AND METHODS
Abstract
Drug delivery systems and methods are disclosed herein. In some
embodiments, a drug delivery system can be configured to deliver a
drug to a patient in coordination with a physiological parameter of
the patient (e.g., the patient's natural cerebrospinal fluid (CSF)
pulsation or the patient's heart or respiration rate). In some
embodiments, a drug delivery system can be configured to use a
combination of infusion and aspiration to control delivery of a
drug to a patient. Catheters, controllers, and other components for
use in the above systems are also disclosed, as are various methods
of using such systems.
Inventors: |
Anand; PJ; (Lowell, MA)
; Brophy; Morgan; (Somerville, MA) ; Singh; Deep
Arjun; (Cambridge, MA) ; Eberl; Greg; (Acton,
MA) ; Arzumand; Ayesha; (North Billerica, MA)
; Moura; Stela; (Lowell, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALCYONE LIFESCIENCES, INC. |
Lowell |
MA |
US |
|
|
Family ID: |
1000004838406 |
Appl. No.: |
16/877065 |
Filed: |
May 18, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15849705 |
Dec 21, 2017 |
10653442 |
|
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16877065 |
|
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|
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62437168 |
Dec 21, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 2005/1726 20130101;
A61B 17/3401 20130101; A61M 27/006 20130101; A61M 2230/005
20130101; A61M 2025/0057 20130101; A61M 2025/0003 20130101; A61M
2025/0007 20130101; A61B 5/032 20130101; A61M 2025/0031 20130101;
A61M 25/0147 20130101; A61B 5/4839 20130101; A61M 2025/0002
20130101; A61B 5/0205 20130101; A61M 2202/0464 20130101; A61M
25/0082 20130101; A61M 2025/09175 20130101; A61M 25/0026 20130101;
A61M 2025/09141 20130101; A61M 2025/0681 20130101; A61M 25/0068
20130101; A61M 2210/1003 20130101; A61M 25/0041 20130101; A61M
5/1723 20130101; A61M 25/0097 20130101 |
International
Class: |
A61B 17/34 20060101
A61B017/34; A61M 5/172 20060101 A61M005/172; A61B 5/03 20060101
A61B005/03; A61B 5/00 20060101 A61B005/00; A61B 5/0205 20060101
A61B005/0205; A61M 25/00 20060101 A61M025/00 |
Claims
1. A drug delivery device, comprising: an elongate body having a
fluid lumen formed therein; and a fluid port formed in the delivery
device, the fluid port being defined by a helical slit formed in a
wall of the delivery device.
2. The device of claim 1, wherein the helical slit extends from an
interior surface of the body to an exterior surface of the
body.
3. The device of claim 1, wherein the helical slit acts as a fluid
communication path between an interior of the fluid lumen and an
exterior of the delivery device.
4. The device of claim 1, wherein the helical slit is formed
through an exterior wall of the delivery device.
5. The device of claim 1, wherein the helical slit is formed in a
sidewall of a reduced-diameter portion of the delivery device.
6. The device of claim 1, wherein the helical slit is formed in a
sidewall of an inner tube that projects from a distal end of the
body.
7. The device of claim 1, wherein the delivery device includes an
atraumatic distal tip defined by a substantially spherical
bulb.
8. The device of claim 1, wherein the delivery device includes a
second, distal-facing fluid port.
9. The device of claim 1, wherein the delivery device includes a
tapered transition between a larger diameter proximal portion of
the delivery device and a reduced diameter distal portion of the
delivery device.
10. The device of claim 9, wherein the tapered transition is at
least one of conical, convex, and concave.
11. The device of claim 1, wherein the delivery device comprises a
catheter.
12. The device of claim 1, wherein the delivery device comprises a
needle.
13. The device of claim 1, further comprising an inflatable member
disposed at a distal end of the delivery device.
14. The device of claim 13, wherein the inflatable member is
deployable from within a sharpened distal tip of the device.
15. The device of claim 13, wherein the inflatable member includes
a fluid port therein.
16. The device of claim 15, wherein the fluid port of the
inflatable member comprises a helical slit.
17. A drug delivery device, comprising: an elongate body having a
fluid lumen therein and a fluid port through which fluid can move
between an interior of the fluid lumen and a location exterior to
the delivery device; wherein at least a portion of the fluid lumen
is helically-shaped.
18. The device of claim 17, wherein the helically-shaped portion of
the fluid lumen is adjacent to the fluid port.
19. The device of claim 17, wherein the helically-shaped portion of
the fluid lumen comprises a tubular passage that defines a
plurality of looped coils.
20. A drug delivery device, comprising: a needle having a sharpened
distal tip; and an inflatable member selectively deployable from a
distal end of the sharpened tip, the inflatable member having a
fluid port formed therein; wherein the fluid port comprises a
helical slit.
21.-30. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/437,168 filed on Dec. 21, 2016, which is hereby
incorporated by reference in its entirety.
FIELD
[0002] Systems and methods are disclosed herein for delivering a
drug to a subject (e.g., via intrathecal delivery into the
cerebrospinal fluid (CSF) or subarachnoid space of the subject's
brain or spine).
BACKGROUND
[0003] There are many instances in which it may be desirable to
deliver a drug to a patient. The term "drug" as used herein refers
to any functional agent that can be delivered to a human or animal
subject, including hormones, stem cells, gene therapies, chemicals,
compounds, small and large molecules, dyes, antibodies, viruses,
therapeutic agents, etc.
[0004] Delivery of the drug can be done in a systemic manner, or
can be targeted to a particular location or a particular
distribution pattern. Targeted drug delivery can be challenging,
however, as there are many instances in which the intended delivery
target is not accessible, or not accessible in a minimally-invasive
manner.
[0005] The natural physiology of the patient can also present drug
delivery challenges. For example, achieving a desired or optimal
drug distribution via intrathecal delivery can be difficult, at
least in part due to the natural flow of CSF within the patient,
which tends to be oscillatory and pulsatile with little net flow.
Traditional techniques which involve delivering a large quantity of
a drug to the intrathecal space and relying on natural diffusion to
distribute the drug are inefficient and may be harmful to the
patient.
[0006] There is a continual need for improved drug delivery systems
and methods.
SUMMARY
[0007] Drug delivery systems and methods are disclosed herein. In
some embodiments, a drug delivery system can be configured to
deliver a drug to a patient in coordination with a physiological
parameter of the patient (e.g., the patient's natural cerebrospinal
fluid (CSF) pulsation or the patient's heart or respiration rate).
In some embodiments, a drug delivery system can be configured to
use a combination of infusion and aspiration to control delivery of
a drug to a patient. Catheters, controllers, and other components
for use in the above systems are also disclosed, as are various
methods of using such systems.
[0008] In some embodiments, a drug delivery device can include an
elongate body having a fluid lumen formed therein; and a fluid port
formed in the delivery device, the fluid port being defined by a
helical slit formed in a wall of the delivery device.
[0009] The helical slit can extend from an interior surface of the
body to an exterior surface of the body. The helical slit can act
as a fluid communication path between an interior of the fluid
lumen and an exterior of the delivery device. The helical slit can
be formed through an exterior wall of the delivery device. The
helical slit can be formed in a sidewall of a reduced-diameter
portion of the delivery device. The helical slit can be formed in a
sidewall of an inner tube that projects from a distal end of the
body. The delivery device can include an atraumatic distal tip
defined by a substantially spherical bulb. The delivery device can
include a second, distal-facing fluid port. The delivery device can
include a tapered transition between a larger diameter proximal
portion of the delivery device and a reduced diameter distal
portion of the delivery device. The tapered transition can be at
least one of conical, convex, and concave. The delivery device can
be or can include a catheter. The delivery device can be or can
include a needle. The delivery device can include an inflatable
member disposed at a distal end of the delivery device. The
inflatable member can be deployable from within a sharpened distal
tip of the device. The inflatable member can include a fluid port
therein. The fluid port of the inflatable member can include a
helical slit.
[0010] In some embodiments, a drug delivery device can include an
elongate body having a fluid lumen therein and a fluid port through
which fluid can move between an interior of the fluid lumen and a
location exterior to the delivery device; wherein at least a
portion of the fluid lumen is helically-shaped.
[0011] The helically-shaped portion of the fluid lumen can be
adjacent to the fluid port. The helically-shaped portion of the
fluid lumen can include a tubular passage that defines a plurality
of looped coils.
[0012] In some embodiments, a drug delivery device can include a
needle having a sharpened distal tip; and an inflatable member
selectively deployable from a distal end of the sharpened tip, the
inflatable member having a fluid port formed therein; wherein the
fluid port comprises a helical slit.
[0013] In some embodiments, a patient-specific infusion method can
include determining a total CSF volume of a patient; aspirating a
volume of CSF from the patient based on the determined total CSF
volume of the patient; and infusing a drug into an intrathecal
space of the patient.
[0014] The method can include, after infusing the drug, infusing
the aspirated CSF of the patient to push the drug in a desired
direction within the intrathecal space. The total CSF volume can be
determined from a pre-operative image of the patient's central
nervous system. The aspirated volume of CSF can be in the range of
about 1% to about 20% of the total CSF volume of the patient. The
drug can be infused while the volume of CSF is aspirated.
[0015] In some embodiments, a drug delivery method can include
inserting a needle into an intrathecal space of a patient;
inserting a fluid delivery catheter through the needle and into the
intrathecal space; infusing a drug through the catheter and into
the intrathecal space; and infusing a chaser through the needle
behind the drug to push the drug through the intrathecal space.
[0016] The chaser can include at least one of a drug, a buffer,
artificial CSF, natural CSF previously aspirated from the patient,
and saline. The chaser can include previously-aspirated CSF. The
CSF can be aspirated and infused using the same syringe in a closed
system. The needle can protrude into the intrathecal space by a
distance in the range of 0 cm to 1 cm. The catheter can protrude
from the needle by a distance in the range of 0 cm to 1 cm.
[0017] In some embodiments, a drug delivery system includes a
catheter having at least one fluid lumen; a pump configured to
infuse fluid through the catheter; a sensor configured to measure a
physiological parameter of a patient; and a controller that
controls the pump to coordinate infusion of a drug through the
catheter with the physiological parameter measured by the
sensor.
[0018] The controller can synchronize infusion frequency with a
frequency of a patient's natural intrathecal pulsation as measured
by the sensor. The controller can synchronize infusion phase with a
phase of a patient's natural intrathecal pulsation as measured by
the sensor. The controller can establish a sinusoidal approximation
of the patient's natural intrathecal pulsation as measured by the
sensor. The controller can synchronize infusions with the ascending
wave of the sinusoidal approximation. The controller can
synchronize infusions with the descending wave of the sinusoidal
approximation. The sensor can be configured to measure intrathecal
pressure. The sensor can include a first sensor configured to
measure intrathecal pressure and a second sensor configured to
measure heart rate. The controller can be operable in a learning
mode in which no infusion is performed and the controller
establishes a correlation between heart rate and intrathecal
pressure based on the output of the first and second sensors; and
an infusion mode in which the controller coordinates infusion of
the drug through the catheter with the intrathecal pulsation of the
patient based on the output of the second sensor. The system can
include an implantable infusion port in fluid communication with
the catheter and an extracorporeal injector configured to mate with
the infusion port. The catheter can include first and second fluid
lumens. The controller can be configured to control the pump to
alternately aspirate fluid through the first fluid lumen and infuse
fluid through the second fluid lumen in coordination with the
physiological parameter measured by the sensor. The sensor can be
configured to measure at least one of heart rate, intrathecal
pressure, intrathecal pulsation rate, respiration rate, lung
capacity, chest expansion, chest contraction, intrathoracic
pressure, and intraabdominal pressure.
[0019] In some embodiments, a method of delivering a drug to a
patient includes inserting a catheter into an intrathecal space of
the patient; measuring a physiological parameter of the patient
using a sensor; and with a controller, controlling a pump to
coordinate infusion of a drug through the catheter with the
physiological parameter measured by the sensor.
[0020] The method can include synchronizing infusion frequency with
a frequency of the patient's natural intrathecal pulsation as
measured by the sensor. The method can include synchronizing
infusion phase with a phase of the patient's natural intrathecal
pulsation as measured by the sensor. The method can include
establishing a sinusoidal approximation of the patient's natural
intrathecal pulsation as measured by the sensor and synchronizing
infusions with an ascending wave of the sinusoidal approximation.
The method can include establishing a sinusoidal approximation of
the patient's natural intrathecal pulsation as measured by the
sensor and synchronizing infusions with a descending wave of the
sinusoidal approximation. The sensor can be configured to measure
intrathecal pressure. The sensor can include a first sensor
configured to measure intrathecal pressure and a second sensor
configured to measure heart rate. The method can include
establishing a correlation between heart rate and intrathecal
pressure based on the output of the first and second sensors when
no infusion is performed; and coordinating infusion of the drug
through the catheter with the intrathecal pulsation of the patient
based on the output of the second sensor. The catheter can include
first and second fluid lumens, and the method can include
controlling the pump to alternately aspirate fluid through the
first fluid lumen and infuse fluid through the second fluid lumen
in coordination with the physiological parameter measured by the
sensor. The sensor can be configured to measure at least one of
heart rate, intrathecal pressure, intrathecal pulsation rate,
respiration rate, lung capacity, chest expansion, chest
contraction, intrathoracic pressure, and intraabdominal pressure.
The catheter can be inserted such that it extends along the spinal
cord of the patient with at least a portion of the catheter being
disposed in the cervical region of the patient's spine and at least
a portion of the catheter being disposed in the lumbar region of
the patient's spine. The method can include delivering a plurality
of different drugs through the catheter, each of the drugs being
delivered through a respective fluid lumen of the catheter. The
method can include, with the controller, controlling the pump to
aspirate fluid through the catheter. The catheter can include a
plurality of outlet ports spaced in a cranial-caudal direction
along the length of the catheter and the method can include
infusing a drug through a first port of the catheter and aspirating
fluid through a second port of the catheter, the second port being
cranial to the first port. The drug can be infused through a port
of the catheter disposed in the cervical region of the patient's
spine to propel the infused drug into the cranial space. The method
can include aspirating a volume of CSF from the patient; infusing a
drug through a first, proximal port of the catheter while
aspirating CSF through a second, distal port of the catheter to
form a bolus of drug between the first and second ports; and
infusing the previously-extracted CSF at a location proximal to the
bolus to urge the bolus in a distal direction. The volume of CSF
aspirated from the patient can be about 10% by volume of the
patient's total CSF. The catheter can be inserted through a
percutaneous lumbar puncture in the patient. The infusion can
include alternating between infusing a first volume of the drug and
aspirating a second volume of the drug, the second volume being
less than the first volume. The drug can be delivered to a target
region, the target region being at least one of an intrathecal
space of the patient, a subpial region of the patient, a cerebellum
of the patient, a dentate nucleus of the patient, a dorsal root
ganglion of the patient, and a motor neuron of the patient. The
drug can include at least one of an antisense oligonucleotide, a
stereopure nucleic acid, a virus, adeno-associated virus (AAV),
non-viral gene therapy, vexosomes, and liposomes. The method can
include at least one of performing gene therapy by delivering the
drug, performing gene editing by delivering the drug, performing
gene switching by delivering the drug, and performing non-viral
gene therapy by delivering the drug. The method can include
determining a total CSF volume of the patient and tailoring the
infusion based on the total CSF volume.
[0021] In some embodiments, a method of delivering a drug to a
patient includes inserting a catheter into an intrathecal space of
the patient; with a controller, controlling a pump to infuse a drug
through the catheter; with the controller, controlling the pump to
aspirate fluid through the catheter; and controlling said infusion
and said aspiration to target delivery of the drug to a target site
within the patient.
[0022] The infusion can override the natural CSF pulsation of the
patient to urge the drug towards the target site. The infusion can
coordinate with the natural CSF pulsation of the patient to urge
the drug towards the target site. The infusion can include
delivering a bolus of the drug and then performing pulsatile
delivery of a fluid behind the bolus to urge the bolus towards the
target site. The fluid can include at least one of a drug, a buffer
solution, and CSF aspirated from the patient through the catheter.
At least a portion of the catheter can be disposed in the target
region. At least one of the infusion and the aspiration can be
coordinated with a physiological parameter of the patient. The
physiological parameter can be at least one of heart rate,
intrathecal pressure, intrathecal pulsation rate, respiration rate,
lung capacity, chest expansion, chest contraction, intrathoracic
pressure, and intraabdominal pressure. The catheter can include
first and second fluid lumens, and the method can include
controlling the pump to alternately aspirate fluid through the
first fluid lumen and infuse fluid through the second fluid lumen.
The catheter can be inserted such that it extends along the spinal
cord of the patient with at least a portion of the catheter being
disposed in the cervical region of the patient's spine and at least
a portion of the catheter being disposed in the lumbar region of
the patient's spine. The method can include aspirating a volume of
CSF from the patient; infusing a drug through a first, proximal
port of the catheter while aspirating CSF through a second, distal
port of the catheter to form a bolus of drug between the first and
second ports; and infusing the previously-extracted CSF at a
location proximal to the bolus to urge the bolus in a distal
direction. The method can include alternating between infusing a
first volume of the drug and aspirating a second volume of the
drug, the second volume being less than the first volume. The
target site can be at least one of an intrathecal space of the
patient, a subpial region of the patient, a cerebellum of the
patient, a dentate nucleus of the patient, a dorsal root ganglion
of the patient, and a motor neuron of the patient. The drug can
include at least one of an antisense oligonucleotide, a stereopure
nucleic acid, a virus, adeno-associated virus (AAV), non-viral gene
therapy, vexosomes, and liposomes. The method can include at least
one of performing gene therapy by delivering the drug, performing
gene editing by delivering the drug, performing gene switching by
delivering the drug, and performing non-viral gene therapy by
delivering the drug. The method can include determining a total CSF
volume of the patient and tailoring the infusion and/or the
aspiration based on the total CSF volume.
[0023] In some embodiments, a drug delivery catheter includes a tip
having a first fluid lumen that extends to a first fluid port, a
second fluid lumen that extends to a second fluid port, and a
guidewire lumen; a hub; and a body having a first fluid tube that
defines a first fluid lumen that is in fluid communication with the
first fluid lumen of the tip, a second fluid tube that defines a
second fluid lumen that is in fluid communication with the second
fluid lumen of the tip, a guidewire having a distal end disposed
within the guidewire lumen of the tip, and a sheath that defines at
least one interior channel in which the guidewire and the first and
second fluid tubes are disposed, wherein the sheath extends from a
distal end of the hub to a proximal end of the tip.
[0024] The tip can have a tapered distal end. The first and second
fluid ports can be offset from a central longitudinal axis of the
tip. At least one of the first and second fluid ports can be aimed
perpendicular to, or at an oblique angle with respect to, the
central longitudinal axis of the tip. The first and second fluid
tubes can extend uninterrupted through the hub. The first and
second fluid tubes can terminate within the hub at respective
connectors to which proximal extension tubes can be selectively
coupled. The guidewire can extend uninterrupted through the hub.
The first and second fluid tubes can have respective fluid
connectors at proximal ends thereof. At least one of the first and
second fluid tubes can be formed from fused silica. At least one of
the first and second fluid tubes can be coated in shrink tubing.
The sheath can be formed form polyurethane. The sheath can include
an opening formed therein in fluid communication with a fluid port
of at least one of the first and second fluid tubes. At least one
of the first and second ports can have a helical interior. At least
one of the first and second ports can have an interior that tapers
towards the distal end of the port. The first fluid port can be
proximal to the second fluid port. The catheter can include an
auger rotatably mounted within the catheter. The catheter can
include a piezoelectric transducer disposed within the
catheter.
[0025] In some embodiments, a percutaneous needle device includes
an elongate shaft that defines at least one lumen therein; a sensor
disposed at a distal end of the elongate shaft; a display mounted
to the elongate shaft configured to display an output of the
sensor; and a connector disposed at a proximal end of the elongate
shaft for making a fluid connection with the at least one
lumen.
[0026] The device can include a fluid reservoir and a flush dome in
fluid communication with the lumen of the needle, wherein actuation
of the flush dome is effective to pump fluid from the reservoir
through the lumen of the needle.
[0027] In some embodiments, a catheter includes an elongate body
having one or more fluid lumens formed therein; and a fluid port
formed in the catheter, the fluid port being defined by a helical
slit formed in a wall of the catheter.
[0028] The catheter can include an atraumatic distal tip defined by
a substantially spherical bulb. The catheter can include a second,
distal-facing fluid port. The helical slit can be formed in a
sidewall of a reduced-diameter portion of the catheter. The
catheter can include a tapered transition between a main body of
the catheter and a reduced-diameter portion of the catheter.
[0029] In some embodiments, a patient-specific infusion method
includes determining a total CSF volume of a patient; aspirating a
volume of CSF from the patient based on the determined total CSF
volume of the patient; and infusing a drug into an intrathecal
space of the patient.
[0030] The method can include, after infusing the drug, infusing
the aspirated CSF of the patient to push the drug in a desired
direction within the intrathecal space. The total CSF volume can be
determined from a pre-operative image of the patient's central
nervous system. The aspirated volume of CSF can be in the range of
about 1% to about 20% of the total CSF volume of the patient. The
drug can be infused while the volume of CSF is aspirated.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 is a schematic view of a drug delivery system;
[0032] FIG. 2 is a perspective view of a catheter that can be used
with the system of FIG. 1;
[0033] FIG. 3A is a perspective view of a tip of the catheter of
FIG. 2;
[0034] FIG. 3B is a sectional view of the tip of the catheter of
FIG. 2;
[0035] FIG. 3C is a series of design views of the tip of the
catheter of FIG. 2;
[0036] FIG. 4 is a sectional view of a body of the catheter of FIG.
2;
[0037] FIG. 5 is a perspective view of a hub of the catheter of
FIG. 2, with a portion of the hub shown as transparent;
[0038] FIG. 6A is a sectional view of the hub of FIG. 5, shown with
integrated connectors;
[0039] FIG. 6B is an end view of the hub of FIG. 5, shown with
integrated connectors;
[0040] FIG. 7A is a plan view of a first bend profile of a
guidewire of the catheter of FIG. 2;
[0041] FIG. 7B is a plan view of a second bend profile of a
guidewire of the catheter of FIG. 2;
[0042] FIG. 7C is a plan view of a third bend profile of a
guidewire of the catheter of FIG. 2;
[0043] FIG. 8A is a perspective, partially-transparent view of a
tip that can be used with the catheter of FIG. 2;
[0044] FIG. 8B is a profile, partially-transparent view of the tip
of FIG. 8A;
[0045] FIG. 9 is a perspective, partially-transparent view of the
body of the catheter of FIG. 2, shown with a side exit port;
[0046] FIG. 10 is a perspective and end view of a tip that can be
used with the catheter of FIG. 2;
[0047] FIG. 11 is a perspective and end view of a tip that can be
used with the catheter of FIG. 2;
[0048] FIG. 12 is a perspective view with a detail,
partially-transparent inset of a catheter that can be used with the
system of FIG. 1;
[0049] FIG. 13 is a perspective view with a detail,
partially-transparent inset of a catheter that can be used with the
system of FIG. 1;
[0050] FIG. 14 is a perspective view with a detail,
partially-transparent inset of a catheter that can be used with the
system of FIG. 1;
[0051] FIG. 15 is a perspective view with a detail,
partially-transparent inset of a catheter that can be used with the
system of FIG. 1;
[0052] FIG. 16 is a schematic view of a focused ultrasound system
that can be used with the system of FIG. 1;
[0053] FIG. 17 is a schematic hardware diagram of a controller of
the system of FIG. 1;
[0054] FIG. 18 is a functional block diagram of the controller of
FIG. 17;
[0055] FIG. 19 is a screen capture of a graphical user interface
that can be implemented by the controller of FIG. 17;
[0056] FIG. 20A is a perspective view of a catheter of the system
of FIG. 1 implanted in a patient and shown with an infusion
port;
[0057] FIG. 20B is a perspective schematic view of the catheter and
patient of FIG. 20A;
[0058] FIG. 20C is a perspective view of the catheter and patient
of FIG. 20A, shown with an infusion port, an injector, and a
controller;
[0059] FIG. 20D is a perspective view of a distal fluid port of the
catheter of FIG. 20A;
[0060] FIG. 20E is a perspective view of a middle or proximal fluid
port of the catheter of FIG. 20A;
[0061] FIG. 21A is a diagram illustrating the controller of the
system of FIG. 1 coordinating control of a pump with a sensed
physiological parameter;
[0062] FIG. 21B is a diagram illustrating use of the system of FIG.
1 to synchronize delivery of a drug with an ascending wave of the
patient's natural CSF pulsation;
[0063] FIG. 21C is a diagram illustrating use of the system of FIG.
1 to synchronize delivery of a drug with a descending wave of the
patient's natural CSF pulsation;
[0064] FIG. 22 is a schematic diagram of a drug delivery system
with a smart lumbar puncture needle;
[0065] FIG. 23 is a schematic diagram of a drug delivery system
with manual pumps;
[0066] FIG. 24A is a schematic view of a drug delivery system;
[0067] FIG. 24B is a perspective view of a needle, hub, and
catheter of the system of FIG. 24A;
[0068] FIG. 24C is a perspective view of a needle, hub, and
catheter of the system of FIG. 24A, shown with the catheter outside
of the needle;
[0069] FIG. 24D is a perspective view of a needle, hub, and
catheter of the system of FIG. 24A, shown with the catheter
inserted through the needle;
[0070] FIG. 24E is a perspective view of a catheter of the system
of FIG. 24A protruding from a needle of the system of FIG. 24A;
[0071] FIG. 24F is a perspective view of a catheter of the system
of FIG. 24A protruding from a needle of the system of FIG. 24A;
[0072] FIG. 24G is a perspective view of a catheter of the system
of FIG. 24A protruding from a needle of the system of FIG. 24A;
[0073] FIG. 25A is a side view of a catheter tip having a helical
fluid port;
[0074] FIG. 25B is a schematic representation of the geometry of
the helical port of FIG. 25A;
[0075] FIG. 25C is a perspective view of the catheter tip of FIG.
25A;
[0076] FIG. 25D is another perspective view of the catheter tip of
FIG. 25A;
[0077] FIG. 25E is a photograph of an exemplary distribution
pattern achieved using the catheter tip of FIG. 25A;
[0078] FIG. 26 is a schematic diagram of an exemplary method of
using the system of FIG. 24A with a patient;
[0079] FIG. 27 is a schematic diagram of an exemplary method of
patient-specific infusion;
[0080] FIG. 28A is a schematic view of a drug delivery system;
[0081] FIG. 28B is a side view of a tip of a needle of the system
of FIG. 28A;
[0082] FIG. 29 is a sectional side view of a tip of another needle
that can be used with the system of FIG. 28A;
[0083] FIG. 30A is a schematic view of a tip of another needle that
can be used with the system of FIG. 28A;
[0084] FIG. 30B is a schematic view of the needle tip of FIG. 30A
with an inflatable member deployed therefrom; and
[0085] FIG. 30C is a schematic view of the needle tip of FIG. 30A
with a fluid being infused through the inflatable member.
DETAILED DESCRIPTION
[0086] Drug delivery systems and methods are disclosed herein. In
some embodiments, a drug delivery system can be configured to
deliver a drug to a patient in coordination with a physiological
parameter of the patient (e.g., the patient's natural cerebrospinal
fluid (CSF) pulsation or the patient's heart or respiration rate).
In some embodiments, a drug delivery system can be configured to
use a combination of infusion and aspiration to control delivery of
a drug to a patient. Catheters, controllers, and other components
for use in the above systems are also disclosed, as are various
methods of using such systems.
[0087] Certain exemplary embodiments will now be described to
provide an overall understanding of the principles of the
structure, function, manufacture, and use of the methods, systems,
and devices disclosed herein. One or more examples of these
embodiments are illustrated in the accompanying drawings. Those
skilled in the art will understand that the methods, systems, and
devices specifically described herein and illustrated in the
accompanying drawings are non-limiting exemplary embodiments. The
features illustrated or described in connection with one exemplary
embodiment may be combined with the features of other embodiments.
Such modifications and variations are intended to be included
within the scope of the present disclosure.
[0088] In some embodiments, systems and methods are provided in
which a drug is injected or otherwise delivered to the central
nervous system of a patient in coordination with the natural CSF
flow. For example, the drug can be injected in a plurality of
stages synchronized in phase and/or frequency with the natural CSF
pulse. The systems and methods herein can allow for a drug to be
delivered more efficiently to a patient than in the case of
traditional techniques. For example, a smaller quantity of the drug
can be delivered and still reach the target destination, thereby
reducing cost and/or possible side effects of delivering a large
quantity of the drug.
[0089] The systems and methods disclosed herein can be used in
applications where the intended delivery target is not accessible
or not accessible in a minimally-invasive manner, but instead more
readily-accessible and safer injection sites which are in direct
fluid communication with the intended delivery site exist. For
example, a drug can be delivered to the intrathecal space of a
patient via an injection site in the patient's spine (e.g., a
lumbar region, a thoracic region, a cervical region, and so forth)
and can be transported via the intrathecal space to a target
location that is cranial to the injection site (e.g., the brain or
a more-cranial region of the spine). In other embodiments, the drug
can be transported to a location that is caudal to the injection
site.
[0090] The systems and methods disclosed herein can include fully
programmable customized injection and/or aspiration profiles which
can be synchronized by real-time monitoring of physiological
parameters of the patient, such as heart rate, CSF pressure, CSF
pulsation rate, respiration rate, lung capacity, chest expansion
and contraction, intrathoracic pressure, intraabdominal pressure,
and the like. This can allow the end user to fine-tune
injection/aspiration doses per cycle, time length and profile of
each microinjection, relative timing (or phase) of microinjections,
and other parameters. The systems and methods disclosed herein can
include real-time inline pressure sensing for estimating drug
delivery efficiency and ensuring patient safety.
[0091] The systems and methods disclosed herein can include custom
built catheters with various lumen quantities, lumen sizes, port
placement locations, and other properties. The catheters can be
directionality-optimized for efficient mixing and/or such that they
are adapted for a particular anatomy.
[0092] FIG. 1 is a schematic diagram of an exemplary drug delivery
system 100. As shown, the system 100 can include a catheter 102, a
controller 104, a pump or actuator 106, and one or more sensors
108. The pump 106 can be configured to pump a drug or a
drug-containing fluid through the catheter 102 and into a patient
110 (e.g., into an intrathecal space of the patient). The pump 106
can also be configured to aspirate fluid from the patient. The pump
106 can be controlled by the controller 104 to synchronize or
otherwise coordinate delivery of the drug and/or aspiration of
fluid with a physiological parameter of the patient, which can be
measured by the sensor 108. Exemplary physiological parameters can
include heart rate, CSF pressure, CSF pulsation rate, respiration
rate, lung capacity, chest expansion and contraction, intrathoracic
pressure, intraabdominal pressure, and the like.
[0093] An exemplary catheter 102 which can be used with the system
100 is shown in FIG. 2. The catheter 102 can include a tip portion
112, a body 114, and a hub 116. A first portion 114d of the body
114 can extend between the tip 112 and the distal end of the hub
116. A second portion 114p of the body 114 can extend proximally
from the hub 116 to one or more connectors 118 or other features
for coupling the catheter 102 to the system 100, e.g., for
attaching the catheter to the pump 106. The catheter 102 can have
an overall length of about 1 meter.
[0094] The tip 112 of the catheter 102 is shown in more detail in
FIGS. 3A-3C. The tip 112 can include a generally cylindrical body
with a conical, bulleted, or tapered tip. The tip 112 can provide
an atraumatic lead-in surface to facilitate tunneling the catheter
102 through tissue or through a lumen of the patient, such as the
intrathecal space. The tip 112 can include one or more fluid lumens
formed therein, and a corresponding one or more fluid ports through
which fluid can be communicated from the fluid lumen to an exterior
of the catheter and vice-versa. In the illustrated embodiment, the
tip 112 includes a first fluid lumen 120A with a first fluid port
122A and a second fluid lumen 120B with a second fluid port 122B,
though it will be appreciated that the tip can include any number
of fluid lumens (e.g., zero, one, two, three, four, five, more than
five, etc.) and any number of fluid ports (e.g., zero, one, two,
three, four, five, more than five, etc.). The fluid ports 122A,
122B can be aimed in a substantially distal direction and can be
offset from the central longitudinal axis of the tip 112, as shown.
In other embodiments, the fluid ports 122A, 122B can be aimed
laterally, e.g., in a direction substantially perpendicular to the
central longitudinal axis of the tip 112. Having the fluid ports
slightly offset from center or aimed laterally can advantageously
reduce the risk of the ports becoming occluded during insertion or
use of the catheter 102.
[0095] The catheter 102 can include a steering mechanism to
facilitate remote positioning of the catheter within the patient.
For example, the catheter 102 can be configured to receive a
guidewire 124 therethrough to allow the catheter to be inserted
over the guidewire or to be steered by the guidewire. In the
illustrated embodiment, the tip 112 includes a guidewire lumen 126.
The guidewire lumen 126 can be a closed, blind hole as shown, or
can be open to an exterior of the tip 112. Alternatively, or in
addition, the catheter 102 can include one or more steering wires
(not shown) that terminate at the tip 112. The wires can extend
proximally from the tip 112 to a proximal end of the catheter 102,
where they can be selectively tensioned to steer the tip of the
catheter within the patient. For example, the catheter 102 can
include first and second steering wires that extend longitudinally
therethrough and which are anchored to the tip 112 at
diametrically-opposed locations about the outer periphery of the
tip. The steering wires can extend through respective sleeves or
tubes in the body 114 of the catheter 102 to the proximal end of
the catheter where tension can be selectively applied thereto to
steer the tip 112 of the catheter.
[0096] The tip 112 can be formed from various materials, including
biocompatible materials, stainless steel, titanium, ceramics,
polymers, and the like. The tip 112 can be radiopaque or can
include one or more radiopaque markers to facilitate visualization
under fluoroscopy or other imaging techniques.
[0097] The tip 112 can have an outside diameter of about 3 French
to about 5 French. The tip 112 can have an outside diameter of
about 1 mm to about 3 mm.
[0098] FIG. 4 is a cross-sectional view of the distal portion 114d
of the catheter body 114. As shown, the body 114 can include an
outer sheath 128 that defines an interior channel 130. One or more
fluid tubes 132A, 132B can be disposed within the interior channel,
each fluid tube defining a respective fluid lumen 134A, 134B. The
interior channel 130 can also contain a guidewire 124 or one or
more steering wires (not shown). In the illustrated embodiment, the
distal body portion 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 a guidewire 124.
[0099] The sheath 128 can have various cross-sectional profiles.
For example, the sheath 128 can have a circular transverse
cross-section that defines a single interior channel 130 as shown.
By way of further example, the sheath 128 can have multiple
interior channels. Each of the fluid tubes 132A, 132B can be
disposed within its own independent channel of the sheath 128, or
the sheath itself can define the fluid tubes. The guidewire 124 can
be disposed in its own independent channel of the sheath 128 and
the fluid tubes 132A, 132B can be disposed in a separate channel of
the sheath. The guidewire channel can have a circular cross-section
and the fluid tube channel can have a crescent or D-shaped
cross-section.
[0100] The fluid tubes 132A, 132B can be formed from any of a
variety of materials, including fused silica, polyurethane, etc.
Use of fused silica can be advantageous when using the system 100
to deliver viruses, as viruses may be less prone to sticking to
fused silica fluid tubes. In some embodiments, fluid tubes used for
drug delivery can be formed from fused silica and fluid tubes not
used for drug delivery (e.g., buffer delivery tubes or aspiration
tubes) can be formed from a material other than fused silica, such
as polyurethane. The fluid tubes 132A, 132B can be coated with a
shrink tubing or an outer sheath to provide stress and strain
relief for the fluid tubes. The sheath 128 can be formed from any
of a variety of materials, including polyurethane. While use of the
fluid tubes 132A, 132B to communicate fluid is generally described
herein, the fluid tubes can also be used for other purposes, such
as inserting a biopsy probe or other instrument, or inserting a
sensor 108.
[0101] The fluid tubes 132A, 132B can have an inside diameter of
about 0.005 inches to about 0.050 inches. The fluid tubes 132A,
132B can have an inside diameter of about 0.010 inches to about
0.020 inches. The body 114 can have an outside diameter of about 3
French to about 5 French. The body 114 can have an outside diameter
of about 1 mm to about 3 mm.
[0102] An exemplary hub 116 is shown in FIG. 5. The hub 116 can
include respective channels for receiving the first fluid tube
132A, the second fluid tube 132B, and the guidewire 124. Each
channel can include proximal and distal openings. The channels can
merge within the body of the hub 116 such that they each share a
common distal opening. The sheath 128 of the distal body portion
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
can penetrate the sidewall of the sheath 128 within the body of the
hub 116. The hub 116 can thus form a seal between the sheath 128
and the fluid tubes 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 114d.
[0103] The hub 116 can be a "pass-through" type hub in which the
first and second fluid tubes 132A, 132B extend completely through
the hub uninterrupted as shown in FIG. 5. Alternatively, as shown
in FIGS. 6A-6B, the first and second fluid tubes 132A, 132B can
terminate within the hub at respective connector ports 136A, 136B.
The connector ports 136A, 136B can allow selective coupling and
decoupling of the proximal body portion 114p (e.g., proximal
extension tubes) to the first and second fluid tubes 132A, 132B.
The guidewire 124 can continue to extend completely through the hub
116 uninterrupted, or it too can terminate within the hub at a
connector where a proximal guide wire extension can be selectively
coupled thereto. Any of a variety of connector types can be used to
couple the fluid tubes to the proximal extension tubes, including
zero-dead-volume micro-connectors or fittings available from Valco
Instruments Co. Inc. of Houston, Tex.
[0104] The proximal body portion 114p can include a sheath similar
to that of the distal body portion 114d, or can be formed by the
fluid tubes 132A, 132B extending proximally from the hub 116, or
from one or more extension tubes coupled to the fluid tubes 132A,
132B at the hub 116. The proximal end of the catheter 102 can
include one or more connectors 118 for making a fluid connection
with the fluid tubes 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) can include a connector 118 at a proximal
end thereof. Any of a variety of connector types can be used,
including zero-dead-volume micro-connectors or fittings available
from Valco Instruments Co. Inc. of Houston, Tex.
[0105] The guidewire 124 can be disposed within the catheter 102
and can be used to guide, steer, or otherwise control insertion of
the catheter into the patient.
[0106] The guidewire 124 can be cylindrical and can have a
substantially-straight profile. The guidewire 124 can extend
completely through the catheter 102, or can terminate in a blind
bore 126 formed in the tip 112 of the catheter. In use, the
guidewire 124 can be inserted into the patient first and guided to
a target site, and the catheter 102 can then be inserted over the
guidewire to position a portion of the catheter at the target site.
In other embodiments, the catheter 102 can be inserted before or
simultaneously with the guidewire 124, and the guidewire can be
used to steer or guide the catheter.
[0107] For example, as shown in FIGS. 7A-7C, the guidewire 124 can
have a resting configuration that deviates from a straight line at
or near a distal end of the guidewire. In FIG. 7A, the guidewire
124 has a straight distal portion 124d and a straight proximal
portion 124p joined by a curved elbow such that a central
longitudinal axis of the distal portion extends at an oblique angle
with respect to a central longitudinal axis of the proximal
portion. In FIG. 7B, the guidewire 124 has a curved distal portion
124d joined to a straight proximal portion 124p such that a central
longitudinal axis of the distal portion extends at an oblique angle
with respect to a central longitudinal axis of the proximal
portion. In FIG. 7C, the guidewire 124 has a straight distal
portion 124d and a straight proximal portion 124p that meet at an
angled bend such that a central longitudinal axis of the distal
portion extends at an oblique angle with respect to a central
longitudinal axis of the proximal portion.
[0108] In use, the guidewire 124 can be used to navigate the
catheter 102 through the patient by twisting the proximal end of
the guidewire to turn the bent distal portion and thereby steer or
aim the catheter. While a single guidewire 124 is shown, it will be
appreciated that the catheter 102 can include any number of
guidewires and/or guidewire lumens. The guidewire 124 can be formed
from any of a variety of materials, including shape-memory metals
such as Nitinol.
[0109] Any of the catheters disclosed herein can be steerable. For
example, a steering mechanism can be provided to allow the distal
end of the catheter 102 to be guided during insertion or at another
desired time. In some embodiments, the catheter 102 can include one
or more steering wires having a first end coupled to the distal tip
112 of the catheter and having a second end at the proximal end of
the catheter through which tension can be selectively applied to
the steering wires to direct or steer the tip of the catheter in a
desired direction. The steering wires can be embedded in the
sidewalls of the catheter 102 or can extend through a lumen of the
catheter.
[0110] In some embodiments, the catheter 102 can include a coaxial
steering catheter (not shown) extending therethrough. A distal end
of the steering catheter can be curved or biased towards a curved
shape such that, when the steering catheter is deployed distally
from the tip of the primary catheter 102, the primary catheter can
be steered or guided along the curve of the steering catheter. The
steering catheter can then be retracted back into the primary
catheter 102 to discontinue the curved guidance. The steering
catheter can be formed from or can include shape memory or
resilient materials such that the steering catheter is deformable
between a substantially straight line configuration when retracted
into the primary catheter 102 and a flexed or curved configuration
when deployed from the primary catheter. The steering catheter can
be longitudinally translatable relative to the primary catheter 102
to allow for deployment and retraction.
[0111] Any of the catheters disclosed herein can include a camera
or imaging device, which can be integral with the catheter or can
be inserted through a working channel of the catheter. Any of the
catheters disclosed herein can include markings visible under
fluoroscopy, CT, MRI, or other imaging techniques to allow the
catheter to be visualized in images captured using such
techniques.
[0112] The catheter 102 can be configured to withstand high
internal pressures. The catheter 102 can be configured to withstand
a pressure of at least about 100 psi, at least about 200 psi,
and/or at least about 500 psi.
[0113] It will be appreciated that a number of variations on the
above-described catheter 102 are possible. For example, one or more
of the fluid ports can be aimed to the side such that they exit a
lateral sidewall of the catheter. FIGS. 8A-8B illustrate an
exemplary catheter tip having side-facing ports. As shown, the tip
112 includes a first fluid lumen 120A that extends to a
distal-facing port 122A. The distal-facing port 122A can be formed
in an angled or slash-cut distal face of the tip 112. The tip 112
also includes a second fluid lumen 120B that extends to a
side-facing port 122B. The tip 112 can also include a guidewire
lumen for receiving the distal end of a guide wire 124. In some
embodiments, the central channel 130 of the sheath 128 can act as a
fluid lumen, e.g., for delivering a buffer or for delivering a
drug. The tip 112 can include a side-facing port 122C in fluid
communication with the central channel 130 of the sheath 128.
[0114] The catheter 102 can include one or more fluid ports formed
proximal to the tip portion 112 of the catheter, e.g., formed in
the body 114 of the catheter. FIG. 9 illustrates an exemplary
catheter body 114 having a side-facing port 122B. As shown, one or
more of the fluid tubes 132A, 132B extending through the sheath 128
of the body 114 can terminate within the body or can otherwise have
a fluid port disposed in the body. The sheath 128 can have a slit
or opening 122B aligned with the port of the fluid tube 132B, such
that fluid exiting the fluid tube can flow through the opening in
the sheath or such that fluid can flow through the sheath and into
the port of the fluid tube. The catheter 102 can include one or
more plugs 138 disposed within the channel 130 of the sheath 128 to
prevent fluid exiting or entering the fluid tube 132B from flowing
proximally and/or distally within the sheath, instead guiding the
fluid out of the sheath through the opening or slit 122B formed
therein, or guiding incoming fluid into the fluid port of the tube.
The plugs 138 can be formed from a rigid material, from an
adhesive, silicone, or various other materials.
[0115] The fluid lumens of the catheter can have various internal
geometries to control or direct the delivery pattern of fluid
delivered therethrough. FIG. 10 illustrates an exemplary catheter
tip 112 in which one of the fluid lumens 120A has a thread formed
on an interior surface thereof to define a helical or "corkscrew"
shape. The helical shape of the fluid lumen 120A can promote
turbulent flow of fluid therefrom encouraging dispersion or even
distribution of the fluid. It will be appreciated that more than
one of the fluid lumens can have a helical tip. FIG. 11 illustrates
an exemplary catheter tip 112 in which one of the fluid lumens 120A
tapers or narrows towards the distal end to create a nozzle. This
nozzle can create a jet-stream effect, increasing the velocity of
the infusate as it is delivered. It will be appreciated that more
than one of the fluid lumens can have a nozzle tip. As also shown
in FIGS. 10-11, one or more of the fluid lumens can have a simple
cylindrical tip.
[0116] As noted above, the catheter 102 can include any number of
lumens extending therethrough. In some embodiments, a dual-lumen
catheter can be used. The dual lumen catheter can include an
infusion lumen and a pressure sensor lumen, an infusion lumen and
an aspiration lumen, two infusion lumens, etc. In other
embodiments, a tri-lumen catheter can be used. The tri-lumen
catheter can include an infusion lumen, an aspiration lumen, and a
pressure sensor lumen, two infusion lumens and an aspiration lumen,
three infusion lumens, etc. FIG. 10 illustrates an exemplary
tri-lumen catheter having an infusion lumen 120A, an aspiration
lumen 120B, and a pressure sensor lumen 120C. FIG. 11 illustrates
an exemplary dual-lumen catheter an infusion lumen 120A and an
aspiration lumen 120B.
[0117] The catheter can include a valve system to control the
direction of fluid flow therethrough. For example, a valve system
can include one-way valves on each lumen to prevent infusion into
an aspiration lumen and vice versa. The valve system can facilitate
use of a single syringe or other pump to infuse and withdraw fluid,
or can facilitate infusion and aspiration through a single
lumen.
[0118] As discussed further below, the sensor 108 can be mounted to
the catheter 102, formed integrally with the catheter, threaded
through a lumen of the catheter, etc. For example, the catheter 102
can include a sensor 108 embedded in the tip portion 112 of the
catheter, or can include a sensor threaded through a dedicated
sensor lumen of the catheter.
[0119] One or more of the fluid lumens through the catheter can
have fluid ports that are longitudinally offset from fluid ports of
other lumens of the catheter. For example, as shown in FIG. 12, the
catheter 102 can include a first fluid lumen 120A that extends to a
fluid port 122A formed at the terminal distal end of the catheter.
The catheter 102 can also include a second fluid lumen 120B that
extends to fluid ports 122B which are spaced a distance D apart
from the distal end of the catheter in a proximal direction. As
shown, the second fluid lumen 120B can include one or more
side-facing ports 122B. In other embodiments, the second fluid
lumen 120B can include a distal facing port. In use, one of the
fluid lumens 120A, 120B can be used to deliver a drug or other
fluid and the other fluid lumen can be used to aspirate fluid from
the patient. The catheter 102 can thus be used to create a
"push-pull" effect at a target site, in which a drug is infused at
the distal end of the catheter via the first fluid lumen 120A and
then drawn back toward the proximal end of the catheter by the flow
of fluid being aspirated through the second fluid lumen 120B. The
opposite arrangement can also be used, in which the drug is infused
through the proximal port(s) and aspirated through the distal
port(s). A proximal end of the catheter 102 can have first and
second connectors 118A, 118B corresponding respectively to the
first and second fluid lumens 120A, 120B. The offset fluid ports
122A, 122B can be used to coordinate delivery with a physiological
parameter of the patient, such as natural CSF flow. An external
peristaltic pump or other device can be used to drive the infusion
and/or aspiration. As shown, the outer sheath 128 of the body 114
can taper inward to the first lumen 120A after the termination of
the second lumen 120B.
[0120] The catheter 102 can include features for controlling
delivery of fluid through the catheter. For example, as shown in
FIG. 13, the catheter 102 can include an internal auger 140. The
auger 140 can have an elongate flexible shaft 142 that extends
through the catheter 102 to a proximal end of the catheter, where
it can be coupled to a motor for driving rotation of the auger. The
motor can be part of the controller 104 or can be a separate
component. The controller 104 can start and stop rotation of the
auger 140, and/or can control the speed or direction of auger
rotation to control delivery of fluid through the fluid lumen 120
in which the auger is disposed. The auger 140 can be disposed in a
fluid tube 132 extending through a sheath portion 128 of the
catheter 102. The auger 140 can also be disposed distal to a
terminal distal end of a fluid tube 132, with the auger shaft 142
extending through the fluid tube. The auger 140 can thus be
disposed within the sheath 128 of the catheter 102 but distal to a
fluid tube 132 of the catheter. The auger 140 can advantageously
control fluid delivery through the catheter 102 and generate more
turbulent flow of fluid from the catheter. A proximal end of the
catheter can have first and second connectors 118A, 118B
corresponding respectively to the first and second fluid lumens and
a third port or connector 118C through which the auger shaft 142
can extend. The auger 140 can be used to coordinate delivery with a
physiological parameter of the patient, such as natural CSF
flow.
[0121] By way of further example, as shown in FIG. 14, the catheter
102 can include an internal, reciprocating piston or inner tube
144. The catheter 102 can include a fixed outer tube 128 and a
slidable inner tube 144 disposed coaxially within the outer tube.
The inner tube 144 can be configured to translate longitudinally
with respect to the outer tube 128. The inner tube 144 can include
a valve 146, e.g., at a terminal distal end thereof. Exemplary
valves include one-way valves, duck-bill valves, spring-biased
check valves, and the like. A seal can be formed between the inner
tube 144 and the outer tube 128, e.g., at a proximal end of the
catheter 102. In use, the inner tube 144 can be loaded with a
drug-containing fluid. The inner tube 144 can then be pulled
proximally with respect to the outer tube 128 to cause the
drug-containing fluid to flow through a one-way valve 146 into the
distal end of the outer tube. The inner tube 144 can then be pushed
distally, closing the one-way valve 146 and expelling the
drug-containing fluid out of the distal end of the outer tube 128
and into the patient. The translating tubes 128, 144 can allow a
fixed or predetermined volume of drug-containing infusate to be
delivered with each reciprocation of the inner tube 144. The
proximal ends of the outer and inner tubes 128, 144 can include
connectors 118A, 118B, e.g., for supplying fluid to the outer and
inner tubes. The reciprocating inner tube 144 can be used to
coordinate delivery with a physiological parameter of the patient,
such as natural CSF flow.
[0122] As another example, as shown in FIG. 15, the catheter 102
can include a transducer 148, such as a piezoelectric transducer,
to help control delivery of a drug through the catheter. The
transducer 148 can be formed on a flex circuit or other substrate
disposed adjacent to a fluid port 122 of the catheter 102. The
transducer 148 can include an electrically-conductive lead or wire
150 that extends proximally therefrom through the catheter 102 to
the controller 104. In use, an electric potential can be applied to
the transducer 148 to induce vibration or other movement of the
transducer. This movement can control distribution of the drug from
the catheter 102. For example, the transducer 148 can control the
direction in which the infusate flows as it exits the catheter 102,
can control the opening or closing of a fluid port 122 of the
catheter, and/or can control the volume of infusate that exits the
catheter. A proximal end of the catheter 102 can have first and
second connectors 118A, 118B corresponding respectively to first
and second fluid lumens and a third port or connector 118C through
which the electrical conductor 150 of the transducer 148 can
extend. The transducer 148 can be used to coordinate delivery with
a physiological parameter of the patient, such as natural CSF
flow.
[0123] The system 100 can include one or more transducers for
delivering focused ultrasound to the patient. As shown in FIG. 16,
a focused ultrasound system 152 can aim ultrasonic waves toward a
location at which drug-containing infusate 154 exits the catheter
102. The focused ultrasound can enhance dispersion of the drug,
and/or control the direction and degree to which the drug
disperses. Focused ultrasound can be used to coordinate delivery
with a physiological parameter of the patient, such as natural CSF
flow. Focused ultrasound can also be used to enhance or direct drug
distribution without pulsatile delivery.
[0124] FIG. 17 illustrates a block diagram of the physical
components of an exemplary embodiment of the controller 104.
Although an exemplary controller 104 is depicted and described
herein, it will be appreciated that this is for sake of generality
and convenience. In other embodiments, the controller 104 may
differ in architecture and operation from that shown and described
here. The controller 104 can be a tablet computer, mobile device,
smart phone, laptop computer, desktop computer, cloud-based
computer, server computer, and so forth. One or more portions of
the controller 104 can be implanted in the patient. Delivery
control software can execute on the controller 104. The software
can execute on a local hardware component (e.g., a tablet computer,
smart phone, laptop computer, or the like) or can execute remotely
(e.g., on a server or cloud-connected computing device in
communications coupling with the controller).
[0125] The illustrated controller 104 includes a processor 156
which controls the operation of the controller 104, for example by
executing embedded software, operating systems, device drivers,
application programs, and so forth. The processor 156 can include
any type of microprocessor or central processing unit (CPU),
including programmable general-purpose or special-purpose
processors and/or any of a variety of proprietary or
commercially-available single or multi-processor systems. As used
herein, the term processor can refer to microprocessors,
microcontrollers, ASICs, FPGAs, PICs, processors that read and
interpret program instructions from internal or external memory or
registers, and so forth. The controller 104 also includes a memory
158, which provides temporary or permanent storage for code to be
executed by the processor 156 or for data that is processed by the
processor. The memory 158 can include read-only memory (ROM), flash
memory, one or more varieties of random access memory (RAM), and/or
a combination of memory technologies. The various components of the
controller 104 can be interconnected via any one or more separate
traces, physical busses, communication lines, etc.
[0126] The controller 104 can also include an interface 160, such
as a communication interface or an I/O interface. A communication
interface can enable the controller 104 to communicate with remote
devices (e.g., other controllers or computer systems) over a
network or communications bus (e.g., a universal serial bus). An
I/O interface can facilitate communication between one or more
input devices, one or more output devices, and the various other
components of the controller 104. Exemplary input devices include
touch screens, mechanical buttons, keyboards, and pointing devices.
The controller 104 can also include a storage device 162, which can
include any conventional medium for storing data in a non-volatile
and/or non-transient manner. The storage device 162 can thus hold
data and/or instructions in a persistent state (i.e., the value is
retained despite interruption of power to the controller 104). The
storage device 162 can include one or more hard disk drives, flash
drives, USB drives, optical drives, various media disks or cards,
and/or any combination thereof and can be directly connected to the
other components of the controller 104 or remotely connected
thereto, such as through the communication interface. The
controller 104 can also include a display 164, and can generate
images to be displayed thereon. In some embodiments, the display
164 can be a vacuum fluorescent display (VFD), an organic
light-emitting diode (OLED) display, or a liquid crystal display
(LCD). The controller 104 can also include a power supply 166 and
appropriate regulating and conditioning circuitry. Exemplary power
supplies include batteries, such as polymer lithium ion batteries,
or adapters for coupling the controller 104 to a DC or AC power
source (e.g., a USB adapter or a wall adapter).
[0127] The various functions performed by the controller 104 can be
logically described as being performed by one or more modules. It
will be appreciated that such modules can be implemented in
hardware, software, or a combination thereof. It will further be
appreciated that, when implemented in software, modules can be part
of a single program or one or more separate programs, and can be
implemented in a variety of contexts (e.g., as part of an embedded
software package, an operating system, a device driver, a
standalone application, and/or combinations thereof). In addition,
software embodying one or more modules can be stored as an
executable program on one or more non-transitory computer-readable
storage mediums. Functions disclosed herein as being performed by a
particular module can also be performed by any other module or
combination of modules, and the controller can include fewer or
more modules than what is shown and described herein. FIG. 18 is a
schematic diagram of the modules of one exemplary embodiment of the
controller 104.
[0128] As shown in FIG. 18, the controller 104 can include a sensor
input module 168 configured to receive information from the
sensor(s) 108. The sensor input module 168 can read and interpret
output signals supplied from the sensors 108 to the processor 156,
e.g., via a general purpose input/output pin of the processor. The
sensor input module 168 can optionally perform various processing
on the sensor signals, such as frequency detection, phase
detection, debouncing, analog-to-digital conversion, filtering, and
so forth.
[0129] The controller 104 can also include a delivery control
module 170 configured to control the pump or actuator 106 to infuse
or aspirate fluid from the patient and/or to control the catheter
102 (e.g., an auger, piston, transducer, ultrasound system, etc.).
For example, when an "infuse" instruction is issued, the delivery
control module 170 can cause power to be supplied to the pump 106
to begin pumping infusate through the catheter 102, or cause an
electronically-actuated valve to open such that infusate stored
under pressure is placed in fluid communication with the catheter
and flows therethrough. In some embodiments, the delivery control
module 170 can be configured to cut off power to the pump 106 or to
close a valve when a pressure sensor indicates that the pressure in
the system has reached a predetermined threshold amount. When an
"aspirate" instruction is issued, the delivery control module 170
can cause power to be supplied to the pump 106 to begin pumping
fluid out of the catheter 102.
[0130] The controller 104 can include a user input module 172
configured to receive one or more user inputs, e.g., as supplied by
a user via the interface 160. Exemplary user inputs can include
infusion parameters, patient information, treatment protocols, and
so forth, as discussed further below.
[0131] The controller 104 can also include a display module 174
configured to display various information to the user on the
display 164, such as a graphical or textual user interface, menus,
buttons, instructions, and other interface elements. The display
module 174 can also be configured to display instructions,
warnings, errors, measurements, and calculations.
[0132] FIG. 19 illustrates an exemplary graphical user interface
176 that can be displayed to the user by the display module 174 and
through which a user can supply information to the user input
module 172. The illustrated interface 176 is configured for use
with a pump system 106 that includes first and second motors or
linear actuators that can be operated to apply a force to
respective syringe pumps for delivering infusate to the catheter
102 and for withdrawing or aspirating fluid from the catheter.
[0133] The user interface 176 can include a motor communication
panel 178 for displaying various information associated with the
motors. This information can include the connection status of the
motors, an IP or other software address of the motors, and a motor
communication frequency or update time. The user can interact with
the motor communication panel 178 to select or change the motor
addresses and the update time.
[0134] The user interface 176 can include a motor setting panel 180
for adjusting various motor settings and for displaying the current
setting to the user. The motor setting panel 180 can include
controls for the motor velocity, motor acceleration, distance of
syringe movement as a function of motor steps, current motor
positions, infusion frequency, infusion amplitude, infusion rate,
infusion phase, and so forth.
[0135] The controller 104 can be configured to control various
infusion and/or aspiration parameters to achieve customized
delivery. This can allow the delivery to be tailored based on the
therapeutic application. Exemplary parameters that can be
controlled by the controller 104 include infusion type, infusion
rate, infusion volume, time between infusions, oscillatory rate,
infusion and withdraw ratio, infusion phase timing, aspiration
type, aspiration rate, time between aspirations, aspiration volume,
and so forth.
[0136] The pump or actuator system 106 can be configured to supply
a drug or a drug-containing fluid to the catheter 102 and/or to
aspirate fluid from the catheter. The system 106 can include one or
more pumps. For example, the system 106 can include a plurality of
pumps, each being associated with and in fluid communication with a
corresponding lumen of the catheter 102. The pumps can also be
associated with and in fluid communication with respective
reservoirs for holding a volume of fluid. In some embodiments, the
system 106 can include first and second syringe pumps coupled to
electronic linear actuators configured to advance or retract the
plungers of the syringe pumps in response to control signals
received from the controller 104. In some embodiments, the system
106 can include a peristaltic pump, an auger pump, a gear pump, a
piston pump, a bladder pump, etc. One or more portions of the
system 106 can be implanted in the patient. The system 106 can
include any of a variety of implantable or extracorporeal pumps. In
some embodiments, the system 106 can include a fully-implanted,
programmable pump and a fully-implanted fluid reservoir containing
fluid to be delivered using the system. In some embodiments, the
entire system 106 can be implantable, e.g., to facilitate chronic
treatment methods.
[0137] The sensor 108 can be a single sensor or a plurality of
sensors. Exemplary sensors include pressure sensors,
electrocardiogram sensors, heart rate sensors, temperature sensors,
PH sensors, respiration rate sensors, respiration volume sensors,
lung capacity sensors, chest expansion and contraction sensors,
intrathoracic pressure sensors, intraabdominal pressure sensors,
and the like. One or more of the sensors 108 can be implanted in
the patient. One or more of the sensors 108 can be mounted on,
inserted through, or formed in or on the catheter 102. The sensors
108 can also be remote from the catheter 102. In some embodiments,
the sensors 108 can include a pressure sensor disposed in or on the
catheter 102 for measuring CSF pressure adjacent to the catheter
and an ECG sensor for measuring the patient's heart rate. The
sensors 108 can be connected (via wires or via a wireless
connection) to the sensor input module 168 of the controller
104.
[0138] As noted above, one or more components of the delivery
system 100 and, in some embodiments, all components of the delivery
system, can be implanted in the patient. Implanting some or all of
the delivery system 100 can facilitate chronic or long-term drug
delivery (e.g., over a period of days, weeks, months, or years) via
non-invasive or outpatient procedures.
[0139] FIGS. 20A-20B illustrate the catheter 102 fully-implanted in
a patient. As shown, the catheter 102 can be configured for
positioning within a patient's intrathecal space and can extend
substantially the entire length of the spinal column or along any
portion thereof. The catheter 102 can include one or more fluid
lumens. The catheter 102 can also include one or more fluid ports.
In some embodiments, the catheter 102 can include a plurality of
fluid lumens, with each of the plurality of fluid lumens having its
own respective fluid port. In the illustrated embodiment, the
catheter 102 includes three fluid lumens and three respective fluid
ports 122P, 122M, and 122D. The catheter 102 can 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. A
proximal end of the catheter 102 can be coupled to a fully
implanted, transcutanous, or extracorporeal infusion port 182
through which fluid can be delivered to (or removed from) the
various lumens of the catheter and through which one or more
sensors 108 on the catheter can be coupled to a controller 104 or
other device. A quick-connector system 184 can be used to couple
the catheter 102 to the infusion port 182. The micro-connector 184
can include air and/or bacterial filters and can be a
zero-dead-volume connector. The pump 106 and the controller 104 can
be mounted together in a chassis or housing 188, as shown in FIG.
20C, which can be coupled to an injector 190 configured to mate
with the infusion port 182. The injector 190 can include magnetic
alignment features 186 for ensuring that the injector is properly
aligned with respect to a subcutaneous infusion port 182.
[0140] As shown in FIG. 20D, the distal or cranial/cervical tip of
the catheter 102 can have a modified shape to encourage turbulent
flow therethrough (e.g., a helical or corkscrew shaped lumen or
fluid port 122D as described above). Any of a variety of other
shapes can be used. The other ports 122M, 122P can be similarly
configured, can have a simple circular cross-section as shown in
FIG. 20E, or can have any other configuration described herein.
[0141] The system 100 illustrated in FIGS. 20A-20E can be used in
acute and/or chronic applications in any of a variety of ways.
[0142] For example, the catheter 102 can be used to deliver three
different drugs (e.g., one drug through each different lumen of the
catheter).
[0143] By way of further example, the catheter 102 can be used for
localized delivery of different drugs to different areas of the
spine.
[0144] As yet another example, the catheter 102 can be used to
deliver the same drug with substantially instantaneous distribution
along the entire spinal column.
[0145] In another example, one port of the catheter 102 can be used
to aspirate while another is used to infuse in order to draw the
infused fluid through the spinal canal. In some embodiments, fluid
can be infused through a lower-lumbar port 122P and fluid can be
aspirated through a cervical port 122D to "pull" the infused fluid
up the spinal column.
[0146] In another example, fluid can be infused through a port 122D
disposed in the cervical region of the patient's spine to propel
infused drug into the cranial space.
[0147] By way of further example, the catheter 102 can be used to
substantially contain an infused drug to a given area of the spine.
In some embodiments, fluid can be infused through a lower-lumbar
port 122P and fluid can be withdrawn from a mid-lumbar port 122M to
keep the infused drug between the two ports 122P, 122M in the
lumbar region of the patient's spine.
[0148] In an exemplary method, infusions and aspirations via
multiple lumens and ports can be staged or combined in a sequence
to create and advance a significant bolus at improved, controlled,
and convenient rates. The method can include simultaneous
aspiration/infusion between deliberately spaced ports. The delivery
can be enhanced by a preparation step of removing a safe amount of
CSF to be replaced in later procedure steps when advancing the
bolus. The method can include a final stage of synchronized
pulsatile infusion. The method can allow a large bolus to be formed
more quickly, can allow controlled dosing, and/or can allow the
bolus to be delivered closer to the brain or other target site. The
method can be performed using a catheter that tapers from the
proximal end towards the distal end. A tapered catheter profile in
which the catheter diameter reduces distal of each port can enable
the catheter to be longer, be easier to introduce/navigate, and
have device reach significantly closer to the target site. Port
designs and locations can be optimized based on dose and other
factors. The catheter can be placed such that fluid exiting the
ports flows against patient anatomy (e.g., a blind lumen end, lumen
sidewall, or lumen constriction) to promote turbulent flow of the
infusate upon exiting the catheter. In an initial step, a volume of
patient CSF can be aspirated through one or more ports of the
catheter. In an exemplary embodiment, about 10% by volume of the
patient's CSF can be aspirated through the catheter and stored in a
reservoir. The amount of CSF that is aspirated can be based on a
clinically-determined safe level. In a subsequent delivery step,
CSF can be aspirated from the patient through a distal fluid port
122D of the catheter 102 while a drug is simultaneously infused
into the patient through a middle port 122M of the catheter. This
can cause a bolus of drug to form between the middle and distal
ports 122M, 122D. The ports can be located along the length of the
catheter to define the bolus size or dose. In an advancement step,
the bolus of drug can be advanced within the patient. This can be
achieved by infusing previously-aspirated CSF from the reservoir
into the patient through a proximal port 122P of the catheter 102.
This infusion can urge the bolus distally towards the target site
and can continue until normal or safe CSF pressure is reached
within the patient. While previously-aspirated CSF is used to
advance the bolus in the above example, other fluid can be used
instead or in addition, such as drug-containing fluid. Before,
during, or after advancement of the bolus, infusion of CSF and/or
drug-containing fluid can be performed in a pulsatile manner in
coordination with one or more physiological parameters of the
patient. The above method can also be performed using only a
proximal port 122P and a distal port 122D. The proximal, middle,
and distal ports 122P, 122M, 122D can be spaced along the length of
the spinal column as shown in FIG. 20A, or can all be contained in
a discrete region of the spine (e.g., the cervical spine, the
thoracic spine, the lumbar spine, etc.).
[0149] The systems disclosed herein can be used in any of a variety
of drug delivery methods.
[0150] In an exemplary method, the infusion pump 106 can be
configured to pump a drug or a drug-containing fluid through the
catheter 102 and into a patient (e.g., into an intrathecal space of
the patient). The catheter 102 can be inserted into the patient at
any of a variety of locations. For example, a percutaneous puncture
can be formed in the patient using a needle. The puncture can be
formed in the lumbar region of the spine, or in any other region of
the spine, e.g., the cervical region between C1 and C2. The needle
can have a bent distal tip that helps steer the catheter 102 to be
parallel to the spinal cord. The catheter 102 can be inserted
through the needle and guided through the intrathecal space along
the spinal cord. The infusion can be performed in proximity to the
percutaneous puncture, or the catheter 102 can be advanced some
distance within the patient. In some embodiments, the catheter 102
can be inserted in the lumbar spine and advanced to the cervical
spine or to the cisterna magna. Infusion can be performed at any
point along the length of the catheter 102. Fluid can be infused
from a distal end of the catheter 102 (e.g., in a cervical region
of the spine), the catheter can be withdrawn proximally, and
further infusion can be performed at a more caudal location (e.g.,
in a lumbar region of the spine).
[0151] The pump 106 can be controlled by the controller 104 to
synchronize or otherwise coordinate delivery of the drug with the
patient's natural CSF flow or pulsation, or with other
physiological parameters of the patient (e.g., heart rate,
respiration rate, lung capacity, chest expansion and contraction,
intrathoracic pressure, intraabdominal pressure, etc.). The
infusion profile can be tailored to override the natural CSF
pulsation to drive the infusate to a target site. Alternatively, or
in addition, the infusion profile can be tailored to coordinate
with and leverage the natural CSF pulsation to move the infusate
towards the target site.
[0152] Readings from a pressure sensor 108 can be received by the
controller 104, which can perform signal processing on the sensor
output to determine various characteristics of the patient's CSF
flow (e.g., phase, rate, magnitude, etc.). The controller 104 can
then control the pump 106 based on these measured characteristics
to deliver a drug in coordination with the natural CSF flow,
optionally synchronizing the delivery in real time. For example, as
shown in the upper portion of FIG. 21A, the controller 104 can
convert the measured pulsatile flow of the CSF into a sinusoidal
approximation. The controller 104 can then output a pump control
signal, as shown in the lower portion of FIG. 21A, to drive the
infusion pump 106 in coordination with the CSF pulsation.
[0153] In some instances, the pressure sensed by the pressure
sensor 108 can be influenced by the infusion through the catheter
102. Accordingly, it can be desirable to have another way of
detecting or estimating CSF flow. Thus, in some embodiments, the
system 100 can be operated initially in a "learning" mode in which
no infusion takes place and the controller 104 establishes a
correlation between CSF pulsation and heart rate (e.g., as detected
by an ECG sensor 108 in communications coupling with the
controller). In general, CSF pulsation tracks heart rate with a
slight delay. Once a correlation is established, the system 100 can
be operated in an "infusion" mode in which infusate is delivered
through the catheter 102 and the CSF pulsation is detected or
estimated based on measured heart rate (instead of or in addition
to detecting or estimating the CSF pulsation based on the pressure
sensor 108 output). In other words, the system 100 can interpolate
or estimate the CSF flow based on the ECG output, without
necessarily having to rely on the pressure sensor output. This can
allow the pressure sensor to be used for other purposes, such as
monitoring the infusion pressure to allow the controller 104 to
automatically regulate delivery to a target pressure or pressure
range.
[0154] In one example use of the systems described herein, a drug
can be delivered to the intrathecal space via a simple bolus
injection (a fast infusion of a volume of fluid) which then just
diffuses slowly along the spinal column.
[0155] In another example, a bolus injection can be performed to
deliver the drug and then the system can be used to create a
pulsation behind the bolus by changing oscillation rate/pulsation
rate to override the natural CSF pulse and make the bolus move more
quickly towards a target location (e.g., the brain). The pulsation
can be created by repeatedly withdrawing or aspirating a volume of
CSF and then pumping that same volume back into the patient to
create a pulse.
[0156] In another example, infusion of the drug itself can be used
to create a pulsation effect to urge the drug along the intrathecal
space. In this example, a first volume of the drug can be infused
(e.g., 0.1 ml) and then a second, smaller volume can be withdrawn
(e.g., 0.05 ml). This can be repeated to create a pulse with a net
infusion on each cycle. The process can be repeated until the
desired dose is delivered. While an infusion-to-withdrawal ratio of
2:1 is discussed above, it will be appreciated that any ratio can
be used. In addition, the rate of infusion and withdrawal can be
controlled (e.g., by infusing quickly and withdrawing slowly) to
create a burst of fluid towards a target location (e.g., the top of
the spinal column).
[0157] In the devices and methods disclosed herein, infusion and/or
aspiration can be coordinated with one or more physiological
parameters of a patient (e.g., natural CSF flow, heart rate,
respiration rate, etc.).
[0158] The direction of drug distribution at an intrathecal target
site can be controlled at least to some degree based on the timing
at which the drug is delivered relative to the timing of the CSF
flow. For example, infusion that is synchronized with the ascending
wave of CSF flow, as shown in FIG. 21B, can be distributed to a
greater degree in the cranial direction whereas infusion that is
synchronized with the descending wave of CSF flow, as shown in FIG.
21C, can be distributed to a greater degree in the caudal direction
of the spinal canal.
[0159] In some embodiments, a dual- or multi-lumen catheter can be
used for alternating, repetitive infusion and aspiration, which can
further enhance drug distribution.
[0160] The systems and methods disclosed herein can provide an
improved means for delivering a drug to the intrathecal space, as
compared with traditional lumbar bolus injections which do not
reach the remote portions of the spinal canal or brain efficiently
(if at all).
[0161] While intrathecal delivery is generally described in the
examples given above, it will be appreciated that the systems and
methods herein can be used in other applications, with appropriate
modification of size or other parameters as will be appreciated by
those having ordinary skill in the art. For example, the systems
and methods disclosed herein can be used for intrarterial or
intravenous delivery. Such systems and methods can include infusion
and/or aspiration that is coordinated with one or more
physiological parameters of a patient (e.g., natural CSF flow,
heart rate, respiration rate, etc.).
[0162] In some embodiments, the drug can be delivered in a
non-pulsatile manner and/or without necessarily coordinating the
delivery with a physiological parameter of the patient. For
example, alternating or otherwise-coordinated aspiration and
infusion can be used to deliver the drug to a target site. By way
of further example, the drug can be infused and then a buffer can
be infused behind the drug to enhance distribution or to move the
drug towards a target site.
[0163] An exemplary method can include inserting at least a portion
of a catheter into a patient and delivering a drug to a target
region of the patient. At least a portion of the catheter can be
disposed in the target region. The drug can be delivered in a
pulsatile manner. The drug can be delivered in coordination with a
physiological parameter of the patient (e.g., the patient's natural
CSF flow and/or the patient's heart rate).
[0164] The target region can be an intrathecal space of the
patient. The target region can be a subpial region of the patient
(e.g., a subpial region of the spinal cord and/or a subpial region
of the brain). The target region can be a cerebellum of the
patient. The target region can be a dentate nucleus of the patient.
The target region can be a dorsal root ganglion of the patient. The
target region can be a motor neuron of the patient. The drug can
include an antisense oligonucleotide. The drug can include a
stereopure nucleic acid. The drug can include a virus. The drug can
include adeno-associated virus (AAV). The drug can include a
non-viral gene therapy. The drug can include vexosomes. The drug
can include liposomes. The method can include performing gene
therapy by delivering the drug (e.g., by delivering a virus such as
AAV). The method can include performing gene editing by delivering
the drug (e.g., by delivering a virus such as AAV). The method can
include performing gene switching by delivering the drug (e.g., by
delivering a virus such as AAV). The method can include performing
non-viral gene therapy by delivering the drug (e.g., by delivering
vexosomes and/or liposomes).
[0165] In some embodiments, the method can include determining a
total CSF volume of the patient and tailoring the delivery based on
the total CSF volume. For example, MRI or other imaging techniques,
with or without contrast, can be used to assess the overall CSF
volume of the patient. The delivery of the drug can then be
tailored based on the measured volume. For example, a larger volume
of buffer can be used with patients having a greater total CSF
volume and a smaller volume of buffer can be used with patients
having a lesser total CSF volume. By way of further example,
infusion amplitude, infusion velocity, aspiration volume,
aspiration amplitude, and other parameters can be varied in
accordance with the measured total CSF volume.
[0166] The infusion volume can range from about 0.05 mL and about
50 mL. The infusion rate can range from about 0.5 mL/min to about
50 mL/min.
[0167] The following are exemplary drug delivery methods that can
be performed using the systems disclosed herein:
Example A
[0168] Alternating Pulsatile infusions of Drug (Pump 1) and
Buffer/Saline (Pump 2)
[0169] Drug Total Volume: 2.2 mL
[0170] Buffer Total Volume: 4.4 mL
[0171] Infusion rate for both pumps: 15 mL/min
[0172] Cycles: 10 cycles at lumbar then 10 cycles at Cisterna
magna
[0173] Time between cycles: 100 milliseconds
[0174] Infusion description: At lumbar section Pump 1 infuses 0.11
mL at 15 mL/min, a 100 ms pause, Pump 2 infuses 0.22 mL at 15
mL/min, a 100 ms pause (cycle 1). This is repeated for a total of
10 cycles at the lumbar. Catheter is threaded up to the cisterna
magna. Pump 1 infuses 0.11 mL at 15 mL/min, a 100 ms pause, Pump 2
infuses 0.22 mL at 15 mL/min, a 100 ms pause (cycle 1). This is
repeated for a total of 10 cycles at the cisterna magna.
Example B
[0175] Alternating Pulsatile infusions of Drug (Pump 1) and
Buffer/Saline (Pump 2)
[0176] Drug Total Volume: 3 mL
[0177] Buffer Total Volume: 20 mL
[0178] Infusion rate for both pumps: 4 mL/min
[0179] Cycles: 13 cycles at thoracic region
[0180] Time between alternating pump 1 to pump 2: 1000
milliseconds
[0181] Time between cycles (pump 2 to pump 1): 5000
milliseconds
[0182] Infusion description: At lumbar section Pump 1 infuses 0.231
mL at 4 mL/min, a 1000 ms pause, Pump 2 infuses 2.0 mL at 4 mL/min,
a 5000 ms pause (cycle 1). This is repeated for a total of 13
cycles at the thoracic region.
Example C
[0183] Alternating Pulsatile infusions of Drug (Pump 1) and
Buffer/Saline (Pump 2)
[0184] Drug Total Volume: 5 mL
[0185] Buffer Total Volume: 8 mL
[0186] Infusion rate for pump 1: 37 mL/min
[0187] Infusion rate for pump 2: 20 mL/min
[0188] Cycles: 5 cycles at thoracic region
[0189] Time between cycles: 10 milliseconds
Infusion description: At lumbar section Pump 1 infuses 1 mL at 37
mL/min, a 10 ms pause, Pump 2 infuses 1.6 mL at 30 mL/min, a 100 ms
pause (cycle 1). This is repeated for a total of 5 cycles at the
thoracic region.
[0190] FIG. 22 illustrates a drug delivery system 200 that includes
a lumbar puncture needle 292. The needle 292 can include a sensor
294 (e.g., a pressure sensor) mounted adjacent a distal tip of the
needle. Accordingly, upon insertion of the needle 292 into the
patient 210, the sensor 294 can measure the pressure or other
properties of the patient's CSF. The needle 292 can also include an
integrated or remote display 296 for displaying the output of the
sensor 294 to a user.
[0191] In some embodiments, the display 296 can be mounted along
the length of the needle 292, distal to a proximal Luer or other
connector 298 of the needle. The needle body 292 can be a tubular
metal shaft with a sharpened or angled tip. Fluid tubing can be
coupled to the needle 292, e.g., via a proximal connector 298, and
to a programmable pump 106. A controller 104 of the type described
above can be programmed to control the pump 106 to deliver fluid
through the needle 292, e.g., in a pulsatile fashion in
coordination with a physiological parameter of the patient. The
needle 292 can be used to deliver a drug, to deliver a buffer,
and/or to aspirate fluid. In some embodiments, a catheter 102 of
the type described above can be inserted through the needle 292 and
the fluid delivery or aspiration can be performed through the
catheter.
[0192] As shown in FIG. 23, a manual pump 206 can be provided
instead of or in addition to the programmable pump 106 and
controller 104 shown in FIG. 22. As shown, a first fluid lumen of
the needle 292 (or of a catheter 102 inserted through the needle)
can be coupled to a first pump 206A that includes a first reservoir
and a first flush dome. Similarly, a second fluid lumen of the
needle 292 (or of a catheter 102 inserted through the needle) can
be coupled to a second pump 206B that includes a second reservoir
and a second flush dome. A user can exert manual finger pressure on
the first and second flush domes to selectively press fluid
contained in the first and second reservoirs into the patient.
Accordingly, the user's manual actuation rate and actuation
pressure can dictate the infusion frequency and volume. A user can
thus pulse the delivery manually. The flush domes can be configured
such that each successive actuation of the dome delivers a fixed
and predetermined volume of fluid. For example, each push of the
flush dome can be configured to deliver 0.1 ml of fluid. In some
embodiments, one of the reservoirs can be filled with a buffer
solution and the other reservoir can be filled with a
drug-containing solution.
[0193] FIGS. 24A-24G illustrate a drug delivery system 300 that can
include a needle 302 and a catheter 304 insertable through the
needle. The needle 302 can be a lumbar puncture needle. The
catheter 304 can be a single lumen catheter or a multi-lumen
catheter. For example, a dual-lumen catheter that bifurcates at a
proximal portion of the catheter can be used as shown. Fluid tubing
306 can be coupled to the catheter 304, e.g., via one or more
proximal connectors 308, and to a programmable pump system 310. The
needle 302 or catheter 304 can also be connected directly to the
pump system 310.
[0194] In some embodiments, the pump system 310 can include first
and second pumps configured to infuse and/or aspirate fluid through
respective lumens of the catheter 304. Any of a variety of pumps
can be used, including a linear-actuator syringe pump of the type
shown in FIG. 24A. A controller 104 of the type described above can
be programmed to control the pump system 310 to deliver fluid
through the catheter 304, e.g., in a pulsatile fashion in
coordination with a physiological parameter of the patient. The
catheter 304 can be used to deliver a drug, to deliver a buffer or
other fluid, and/or to aspirate fluid. In some embodiments, the
catheter 304 can be omitted and fluid can be infused through the
needle 302 directly and/or aspirated through the needle directly.
One or more of the fluid connections can be made with the needle
302 instead of or in addition to the catheter 304. For example, the
fluid tubing through which a drug is to be delivered can be coupled
directly to the catheter 304 to deliver the drug through the
catheter and fluid tubing through which a buffer, chaser, or other
fluid is to be delivered can be coupled directly to the needle 302
to deliver the fluid through the needle.
[0195] The needle 302 can be defined by a hollow tubular body
configured to receive a catheter and/or fluid therethrough. The
needle 302 can be a lumbar puncture needle sized and configured for
insertion into the intrathecal space through a lumbar insertion
point. The needle 302 can have a curved distal tip configured to
naturally steer the needle into the intrathecal space as the needle
is inserted into the patient in the lumbar region of the spine. An
opening can be formed in the distal end of the needle 302 through
which an inserted catheter 304 can extend.
[0196] The proximal end of the needle can be coupled to a fluid hub
312. As shown in FIG. 24B, the hub 312 can be a "W" hub. The hub
312 can include a plurality of ports. The hub 312 can include a
distal port to which the needle 302 can be attached and placed in
fluid communication with the hub. The hub 312 can include one or
more proximal ports. The proximal ports can guide a catheter 304
inserted though the hub 312 into the central lumen of the needle
302. The proximal ports can attach the hub 312 to respective fluid
lines and place the hub in fluid communication with said fluid
lines. The fluid lines can be used to direct fluid into the hub 312
and through a needle 302 attached thereto. The proximal and distal
ports of the hub 312 can be Luer type connectors or
zero-dead-volume connectors. As shown in FIG. 24B, the hub 312 can
include a distal port attached to the needle 302 and a proximal
port through which a dual-lumen catheter 304 is inserted to guide
the catheter through the needle. The dual lumen catheter 304 can
split or bifurcate at a location proximal to the hub 312 into first
and second fluid lines, e.g., for carrying a drug and a buffer,
respectively. The hub 312 can include one or more additional ports
through which a fluid can be introduced into, or withdrawn from,
the needle 302. These ports can be used to deliver drug or buffer
to the needle 302 or to aspirate fluid from the needle, instead of
or in addition to doing so using the catheter 304.
[0197] As shown in FIGS. 24C-24D, the hub 312 can be a "Y" hub. The
hub 312 can include a distal port attached to the needle 302 and a
proximal port through which a dual-lumen catheter 304 is inserted
to guide the catheter through the needle. The dual lumen catheter
304 can split or bifurcate at a location proximal to the hub 312
into first and second fluid lines, e.g., for carrying a drug and a
buffer, respectively. The hub 312 can include one or more
additional ports through which a fluid can be introduced into, or
withdrawn from, the needle 302. These ports can be used to deliver
drug or buffer to the needle 302 or to aspirate fluid from the
needle, instead of or in addition to doing so using the catheter
304.
[0198] In some embodiments, the hub can be omitted and fluid can be
delivered to or aspirated from the needle 302 directly. For
example, the needle 302 can be directly attached to the pump system
310 via one or more fluid lines, or a catheter 304 can be directly
attached to the pump system via one or more fluid lines and
inserted through the needle without a proximal hub.
[0199] The system 300 can include one or more valves to control or
limit fluid flow through the system. For example, the system 300
can include check valves 314 disposed in-line with respective fluid
paths from the pump system 310 to the patient to isolate the paths
from one another in a single direction or in both directions. In an
exemplary arrangement, the system 300 can include first and second
independent fluid sections or channels. The first fluid section or
channel can include a first pump configured to deliver a first
fluid through a first fluid tube and through a first fluid lumen of
the catheter 304. The second fluid section or channel can include a
second pump configured to deliver a second fluid through a second
fluid tube and through a second fluid lumen of the catheter 304. A
first valve, e.g., a check valve, can be disposed in the catheter,
in the first fluid tube, or in the first pump to prevent fluid
being infused or aspirated by the second pump from entering the
first fluid section of the system. Similarly, a second valve, e.g.,
a check valve, can be disposed in the in the catheter, in the
second fluid tube, or in the second pump to prevent fluid being
infused or aspirated by the first pump from entering the second
fluid section of the system. In some embodiments, only one of the
first and second fluid channels includes a valve. The first fluid
section can be used to infuse a drug and the second fluid section
can be used to infuse a fluid, e.g., drug, buffer, chaser, CSF,
artificial CSF, saline, etc. The first fluid section can be used to
infuse a fluid and the second fluid section can be used to aspirate
a fluid.
[0200] The needle 302 or the catheter 304 can include a sensor 314
(e.g., a pressure sensor) mounted adjacent a distal tip of thereof.
Accordingly, upon insertion of the needle 302 or catheter 304 into
the patient, the sensor 314 can measure the pressure or other
properties of the patient's CSF. The needle 302 or catheter 304 can
also include an integrated or remote display for displaying the
output of the sensor 314 to a user. In some embodiments, the
display can be mounted along the length of the needle or catheter,
distal to a proximal hub or other connector. The needle body can be
a tubular shaft with a sharpened or angled tip. A distal end of the
needle can be curved in one or more planes.
[0201] As shown in FIGS. 24E-24G, the catheter 304 can be inserted
through the needle 302 such that a distal end of the catheter
protrudes from the needle. Alternatively, the catheter can be
inserted such that it is recessed relative to the distal end of the
needle, or such that the distal ends of the needle and of the
catheter are flush.
[0202] The needle 302 can have a length in the range of about 2
inches to about 5 inches, e.g., a length of about 3.5 inches. The
hub 312 can have a length in the range of about 1 inch to about 3
inches, e.g., about 2 inches. The needle 302 can have an outside
diameter in the range of about 26 gauge to about 10 gauge, e.g.,
about 17 gauge. The catheter 304 can have an outside diameter in
the range of about 0.020 inches to about 0.125 inches. The needle
302 can have an inside diameter in the range of about 0.020 inches
to about 0.2 inches. The catheter 304 can be inserted through the
needle 302 such that the catheter protrudes from the distal end of
the needle by a protrusion distance. The protrusion distance can be
in the range of about 1 mm to about 5 cm, e.g., about 1 cm. The
protrusion distance can be zero such that the catheter 304 does not
protrude from the needle 302. Limiting the degree to which the
catheter 304 protrudes from the needle 302 can advantageously
obviate the need to thread the catheter through the intrathecal
space. This can be make the delivery procedure safer and/or less
invasive and reduce the level of skill required to use the system
300.
[0203] The catheter 304 can have any of the features of the
catheters described above. FIGS. 25A-25D illustrate an exemplary
catheter 304 that can be used in the system 300. The catheter 304
can include a tubular body 316 that defines one or more fluid
lumens 318. The catheter 304 can include one or more ports 320 that
place the inner fluid lumen 318 of the catheter in fluid
communication with the exterior of the catheter. Fluid can be
infused or aspirated through the ports 320. The illustrated
catheter includes a port 320A in the form of a helical-shaped slit.
FIG. 25B schematically illustrates an exemplary helical-shaped slit
geometry in three-dimensions. The slit 320A can be formed in the
sidewall of the catheter, in the sidewall of a reduced-diameter
distal portion of the catheter, or in the sidewall of an inner tube
projecting from a distal end of the catheter. In embodiments that
include an inner tube, the inner tube can extend the full length of
the catheter or along only a portion of the catheter length. The
inner tube can be affixed to the catheter using an adhesive, sonic
welding, or other techniques. Alternatively, the inner tube can be
formed integrally with the main catheter body, e.g., via a molding
or milling process. The catheter can include a front-facing port
320B. The front-facing port can be defined by a circular opening
formed in a distal-facing end wall of the catheter 304.
[0204] While a helical-shaped slit is shown, the catheter 304 can
alternatively or additionally have ports with other shapes.
Exemplary port shapes include circular holes, a plurality of
discrete holes arranged in a helical pattern about the catheter,
cage or mesh type openings, and so forth. As shown in FIG. 25E, a
helical-shaped slit port 320A can advantageously increase the
dispersion of fluid infused through the catheter 304 into a
surrounding medium.
[0205] The distal end of the catheter 304 can have an atraumatic
geometry. For example, the catheter can include a substantially
spherical or bulb-shaped portion 322 at a distal end thereof as
shown. In embodiments in which the catheter 304 includes a
stepped-down or reduced-diameter portion, the catheter can include
a fillet or flange 324 to transition between the different
diameters. For example, as shown in FIGS. 25C-25D, a tapered
transition can be formed between the reduced distal portion of the
catheter and the enlarged proximal portion of the catheter. The
tapered transition can be conical. The tapered transition can be
convexly or concavely curved.
[0206] The distal portion of the catheter 304 can be formed from,
coated with, or impregnated with a radiopaque, magnetic, or other
image-able material. For example, a separate inner tube in which
the fluid port is formed can be formed from such a material and
attached to the outer catheter body. The image-able material can
facilitate visualization and guidance of the tip of the catheter
under fluoroscopy or other imaging techniques such as MRI, CT, PET,
and the like.
[0207] The catheter 304 can be formed form any of a variety of
materials. Exemplary materials include polyimide, PEEK,
polyurethane, silicone, and combinations thereof.
[0208] The drug delivery system 300 can be used in a manner similar
or identical to the drug delivery systems described above. FIG. 26
illustrates an exemplary method of using the system 300. As shown,
the needle 302 can be inserted percutaneously into a patient in the
lumbar region of the patient's spine, e.g., using standard lumbar
puncture technique. The curved distal end of the needle 302 can
help guide the distal opening of the needle into the intrathecal
space IS without damaging the spinal cord SC. The needle 302 can be
inserted into the intrathecal space only to a small degree, e.g.,
about 1 cm in to the intrathecal space. A catheter 304 can be
inserted through the needle 302 to position a distal tip of the
catheter within the intrathecal space. As noted above, in some
embodiments, the catheter 304 only protrudes from the needle 302 by
a small amount, e.g., by about 1 cm. The proximal end of the
catheter 304 or the needle 302 can be coupled to a pump system 310
for infusing or aspirating fluid through the catheter or the
needle. In some arrangements, the pump system includes separate
drug and buffer channels, each having a respective pump. The pump
system can be coupled to dual lumens of the catheter, e.g., at a
bifurcated proximal portion of the catheter. In other arrangements,
a first channel of the pump system can be coupled to the needle and
a second channel of the pump system can be coupled to the catheter.
In other arrangements, the catheter can be omitted and the pump
system can include a single channel coupled to the needle, or can
include multiple channels coupled to the needle.
[0209] A controller 104, e.g., a programmable computer processor,
or a user can control the pump system 310 to infuse and/or aspirate
fluid from the patient via the catheter and/or needle.
[0210] In an exemplary embodiment, a drug can be infused through a
first fluid channel of the system 300 and, thereafter, a chaser can
be infused through the same or a different fluid channel of the
system to push the drug through the intrathecal space of the
patient. Exemplary chasers include drug-containing fluid, buffer
fluid, artificial CSF, natural CSF previously aspirated from the
patient, saline, etc. In some embodiments, the chaser can be CSF
previously aspirated from the patient and the CSF can be aspirated
and infused using the same syringe without removing the CSF from
the syringe, thereby maintaining a closed sterile system.
[0211] The catheter 304 or needle 302 can include any of the
features of the needle 402 described below.
[0212] FIG. 28A illustrates an exemplary drug delivery system 400
that can be used for intrathecal infusion and/or aspiration of
fluid. The system 400 is substantially similar to the system 300
described above, though in the system 400, fluid is delivered or
aspirated directly through the needle 402, without inserting a
catheter through the needle. The needle 402 can be coupled at a
proximal end thereof to a pump system 410. As in the systems
described above, the pump system 410 can have multiple fluid
channels (e.g., one channel for drug and another channel for
chaser). The pump system 410 can be connected to the needle 402 by
one or more fluid tubes. A hub can be formed on or coupled to the
needle 402 to connect the needle to the fluid tubes. For example, a
Y-connector port can be used to connect the pump system 410 to the
needle 402. The needle 402 can have various diameters and, in an
exemplary embodiment, can be a 22 gauge needle. One or more valves
414 can be disposed in-line in the fluid tubes, in the needle 402,
or in the pump system 410. The valves 414 can be one-way valves,
check valves, etc.
[0213] The needle can have any of a variety of fluid ports formed
therein. For example, as shown in FIGS. 28A-28B, the needle 402 can
include a helical slit fluid port 420A formed adjacent a distal tip
of the needle. The fluid port 420A can be laser-cut. As another
example, as shown in FIG. 29, the needle 402A can have a helical
inner lumen 418 disposed adjacent to a distal fluid port 420B. The
helically-shaped inner lumen 418 can facilitate turbulent flow of
infusate through the distal fluid port to better disperse the
fluid. The helically-shaped inner lumen 418 can be a tubular
passage that defines a plurality of looped coils. The needle 402
can include a sharpened pencil tip. As another example, as shown in
FIGS. 30A-30C, the needle 402B can include an inflatable member
426, e.g., a balloon or membrane, disposed in a distal end of the
needle. The needle 402 can include a sharpened tip. The inflatable
member 426 can be initially retracted within the tip of the needle
402, and the sharpened tip can be used to pierce the patient's dura
D or other tissue to facilitate needle insertion. Once the distal
tip of the needle 402 is positioned in a desired location, e.g.,
within the intrathecal space, the inflatable member 426 can be
deployed outside of the needle, as shown in FIG. 30B. Deployment of
the inflatable member 426 can be achieved by infusing fluid through
the needle 402. The inflatable member 426 can include one or more
fluid ports formed therein, through which fluid can be infused or
aspirated. For example, as shown in FIG. 30C, the inflatable member
426 can include a helical fluid port 420A formed therein through
which fluid can be infused. The inflatable member 426 can be formed
from a soft material, e.g., a material softer than the material
used to form the needle 402, to define an atraumatic tip when the
inflatable member is deployed. The inflatable member 426 can be
formed from a flexible biocompatible material such as silicone.
[0214] The needle 402 can include any of the features of the
catheter 304 or needle 302 described above.
[0215] In some embodiments, volume displacement of CSF can be used
to move an infused drug through the intrathecal space of the
patient. For example, fluid can be aspirated from the intrathecal
space before, during, or after drug infusion to urge the drug in a
desired direction within the intrathecal space. The fluid used for
such volume displacement can be in the range of about 1% to about
20% of the patient's total CSF volume. The fluid can be aspirated
from the patient and then subsequently re-infused.
[0216] The systems disclosed herein can be used for
patient-specific infusion. In an exemplary patient-specific
infusion method, a specific patient's CSF volume can be determined,
for example by calculating or estimating. For example, a
preoperative or intraoperative image of the patient can be
captured. The image can be one or more MRI images of the patient's
head and spine and/or entire central nervous system. Image
processing routines or manual estimation techniques can be used,
e.g., with correlation to a 3D anatomical model, to calculate or
estimate the total CSF volume of the patient. The calculated or
estimated CSF volume can be used to tailor an infusion and/or
aspiration profile to that particular patient. For example, about
1% to about 20% of the calculated or estimated total CSF volume can
be aspirated from the patient and re-infused behind an infused drug
to urge the drug in a desired direction, e.g., cranially or
caudally within the patient's intrathecal space.
[0217] In some embodiments, a method can include measuring the CSF
head to body volume of a human using magnetic resonance imaging or
other means. The method can include therapy or drug infusion
performed by removal and/or infusion of 0.5 to 20% of the patient's
total CSF volume. The method can include therapy or drug infusion
performed by removal and/or infusion of artificial CSF, buffer
solutions, or saline in conjunction with delivery of drug or
therapy. The method can include delivering the drug or therapy at
volume flow rates in the range of about 0.1 ml/min to about 30
ml/min. The drug and additional volume (e.g., aspirated CSF,
artificial CSF, buffer, etc.) can be infused using pulsatile
delivery as disclosed herein and/or using pulsatile delivery based
on a physiological parameter as disclosed herein. The drug and
additional volume can be infused serially or in parallel. Volume
displacement and/or patient-specific drug or therapy infusion can
advantageously provide better biodistribution of the infused
drug.
[0218] FIG. 27 illustrates an exemplary method of patient-specific
infusion. As shown, the method can include determining the
patient's total CSF volume, aspirating a volume of CSF based on the
patient's total CSF volume, and infusing a drug.
[0219] The infusion flow rate of the systems disclosed herein can
be in the range of about 0.001 ml/min to about 50 ml/min.
[0220] U.S. Provisional Application No. 62/159,552 filed on May 11,
2015, U.S. Provisional Application No. 62/239,875 filed on Oct. 10,
2015, U.S. Provisional Application No. 62/303,403 filed on Mar. 4,
2016, and U.S. application Ser. No. 15/151,585 filed on May 11,
2016 are hereby incorporated herein by reference in their
entirety.
[0221] Although the invention has been described by reference to
specific embodiments, it should be understood that numerous changes
may be made within the spirit and scope of the inventive concepts
described. Accordingly, it is intended that the invention not be
limited to the described embodiments.
* * * * *