U.S. patent application number 16/192500 was filed with the patent office on 2019-05-30 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, Andrew East, Greg Eberl, Jonathan Freund, Stela Moura, Deep Arjun Singh.
Application Number | 20190160254 16/192500 |
Document ID | / |
Family ID | 66431620 |
Filed Date | 2019-05-30 |
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United States Patent
Application |
20190160254 |
Kind Code |
A1 |
Anand; PJ ; et al. |
May 30, 2019 |
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; (Boston, MA) ; Singh; Deep
Arjun; (Cambridge, MA) ; Eberl; Greg; (Acton,
MA) ; Arzumand; Ayesha; (North Billerica, MA)
; Moura; Stela; (Lowell, MA) ; East; Andrew;
(Lowell, MA) ; Freund; Jonathan; (Woburn,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALCYONE LIFESCIENCES, INC. |
Lowell |
MA |
US |
|
|
Family ID: |
66431620 |
Appl. No.: |
16/192500 |
Filed: |
November 15, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62586498 |
Nov 15, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/168 20130101;
A61M 25/0147 20130101; A61M 25/003 20130101; A61M 2025/0007
20130101; A61M 2205/0266 20130101; C12N 2320/35 20130101; A61M
5/007 20130101; A61M 39/0208 20130101; A61M 25/0017 20130101; A61M
2005/1726 20130101; C12N 15/111 20130101; A61M 2205/3331 20130101;
A61M 25/0045 20130101; A61M 25/0032 20130101; A61M 2025/1052
20130101; A61M 5/1408 20130101; A61M 2210/1003 20130101; A61M
2205/502 20130101; C12N 2320/32 20130101; A61M 25/1002 20130101;
A61M 2230/06 20130101; C12N 15/113 20130101; A61M 5/172 20130101;
A61M 25/1011 20130101; A61M 2230/42 20130101; A61M 5/14546
20130101; A61M 2210/0693 20130101; C12N 2310/11 20130101; A61M
2205/3303 20130101; A61M 25/09 20130101; A61M 2205/52 20130101;
A61M 5/1723 20130101; A61M 5/19 20130101; A61M 2205/3584
20130101 |
International
Class: |
A61M 25/00 20060101
A61M025/00; A61M 25/10 20060101 A61M025/10; A61M 39/02 20060101
A61M039/02 |
Claims
1. A catheter implantable into a body cavity of a patient, the
catheter comprising: a body extending between a proximal end and a
distal end; at least one lumen extending within the body; a distal
outlet at the distal end of the body; and a plurality of radial
outlets staggered along the length of the body and arrayed about a
circumference of the body.
2. The catheter of claim 1, wherein the plurality of radial outlets
have a total cross-sectional area less than a cross-sectional area
of the distal outlet.
3. The catheter of claim 1, wherein the distal outlet comprises
staggered-bifurcated distal outlets.
4. The catheter of claim 3, further comprising a control wire
coupled to at least one of the staggered-bifurcated distal outlets,
the control wire actuatable to bifurcate the staggered-bifurcated
distal outlets in situ.
5. The catheter of claim 1, wherein the at least one lumen
comprises a plurality of lumens extending within the body.
6. The catheter of claim 5, wherein the distal outlet comprises a
plurality of distal outlets of the plurality of lumens disposed in
an spiral configuration at the distal end of the body.
7. The catheter of claim 5, wherein the plurality of radial outlets
comprise a plurality of radial outlets of one or more of the
plurality of lumens having varying sizes.
8. The catheter of claim 5, wherein the plurality of radial outlets
comprise a helical cut in one or more arcs of a side lumen of the
plurality of lumens.
9. The catheter of claim 5, wherein at least one of the plurality
of lumens has a crescent or arc shaped transverse
cross-section.
10. The catheter of claim 5, wherein one of the plurality of lumens
comprises a dedicated guidewire lumen configured to receive a
removable guide wire therethrough.
11. The catheter of claim 1, further comprising steerable wires
extending within the body.
12. The catheter of claim 1, wherein the body further includes
radio-opaque marks disposed adjacent to one or more of: the distal
outlet, a proximal end of the plurality of radial outlets, or a
distal end of the plurality of radial outlets.
13. The catheter of claim 1, wherein the body comprises a
selectively expandable body.
14. The catheter of claim 13, wherein the selectively expandable
body comprises an outer sheath expandable from a first, bunched
configuration to a second, extended configuration.
15. The catheter of claim 13, wherein the selectively expandable
body comprises a proximal portion configured to be wrapped around a
subcutaneous port, such that rotation of the port causes the body
to expand.
16. The catheter of claim 1, further comprising a retention
mechanism to selectively hold the body in a desired position within
the body cavity.
17. The catheter of claim 16, wherein the retention mechanism
comprises a balloon having a first inflation state in which the
balloon centers the body within the body cavity and allows fluid
flow past the balloon and a second inflation state in which the
balloon occludes the body cavity.
18. The catheter of claim 17, wherein the balloon is coupled to the
body adjacent to the proximal to control or limit flow in the
distal direction or distal end to control or limit flow in the
proximal direction.
19. The catheter of claim 17, wherein the balloon comprises a
plurality of balloons inflatable at the same time to control or
limit flow between the balloons or to hold the therapeutic in the
designated location
20. The catheter of claim 17, wherein the balloon is fixed to the
body.
21. The catheter of claim 16, wherein the retention mechanism
comprises a shape-memory wire extendable from a storage position
within the body to a retention position in a preformed shape to
anchor body within the body cavity.
22. The catheter of claim 1, wherein the body comprises a
multi-layer architecture including an inner liner layer, a
reinforcement layer, and an outer-jacket
23. The catheter of claim 22, wherein the reinforcement layer
comprises a braided or coiled layer.
24. The catheter of claim 23, wherein the reinforcement layer
further comprises steering wires configured to navigate the body
within the body cavity.
25. The catheter of claim 22, wherein the multi-layer architecture
comprises a structural layer having a pattern of perforations
alternating with a hydrophilic or nano-porous layer allowing
localized permeation.
26. The catheter of claim 25, wherein the structural layer
comprises two structural layers defining a reservoir
therebetween.
27. The catheter of claim 25, wherein the hydrophilic or
nano-porous layer contains treatment configured to be released on
contact with a predetermined fluid or with infusion pressure.
28. The catheter of claim 1, wherein the body includes outwardly
extending longitudinal ridges forming longitudinal channels on an
exterior surface of the body to exterior create flow channels.
29. The catheter of claim 1, further comprising one or more dosages
of a therapeutic used to treat one or more of: Parkinson's,
Friedreich's Ataxia, Canavan's disease, ALS, Congenital Seizures,
Drevets Syndrome, pain, SMA, Tauopathies, Huntington's,
Brain/Spine/CNS tumors, inflammation, Hunters, Alzheimer's,
hydrocephalus, Sanfillippa A, B, Epilepsy, Epilepsy pre-visualase,
PCNSL, PPMS, Acute disseminated encephalomyelitis, Rx of motor
fluctuations in advanced Parkinson's patients, Acute repetitive
seizures, Status epilepticus, ERT, or Neoplastic meningitis.
30. The catheter of claim 1, further comprises one or more dosages
of antisense oligonulceotides, Adeno Viruses, Gene therapy (AAVs
and non-AAV) including gene editing and gene switching, Oncolytic
immunotherapies, monoclonal and polyclonal antibodies, stereopure
nucleic acids, small molecules, methotrexate, Edavaronc-conjugate,
Conotoxin, abomorphinc, Prednisolone hcmisuccinate sodium,
Carbidopa/Levodopa, tetrabenazine, BZD (Diazepam and Midazolam),
Alphaxalone or other derivative, Cyclophosphamide, Idursulfase
(Elaprase), Iduronidase (Aldurazyme), Topotecan, or Buslfan.
Description
[0001] This application relates to U.S. Provisional Patent
Application No. 62/437,168, filed on Dec. 21, 2016, which is hereby
incorporated by reference herein 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 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.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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
[0022] FIG. 1 is a schematic view of a drug delivery system;
[0023] FIG. 2 is a perspective view of a catheter that can be used
with the system of FIG. 1;
[0024] FIG. 3A is a perspective view of a tip of the catheter of
FIG. 2;
[0025] FIG. 3B is a sectional view of the tip of the catheter of
FIG. 2;
[0026] FIG. 3C is a series of design views of the tip of the
catheter of FIG. 2;
[0027] FIG. 4 is a sectional view of a body of the catheter of FIG.
2;
[0028] FIG. 5 is a perspective view of a hub of the catheter of
FIG. 2 with a portion of the hub shown as transparent;
[0029] FIG. 6A is a sectional view of the hub of FIG. 5, shown with
integrated connectors;
[0030] FIG. 6B is an end view of the hub of FIG. 5, shown with
integrated connectors;
[0031] FIG. 7A is a plan view of a first bend profile of a
guidewire of the catheter of FIG. 2;
[0032] FIG. 7B is a plan view of a second bend profile of a
guidewire of the catheter of FIG. 2;
[0033] FIG. 7C is a plan view of a third bend profile of a
guidewire of the catheter of FIG. 2;
[0034] FIG. 8A is a perspective, partially-transparent view of a
tip that can be used with the catheter of FIG. 2;
[0035] FIG. 8B is a profile, partially-transparent view of the tip
of FIG. 8A;
[0036] FIG. 9 is a perspective, partially-transparent view of the
body of the catheter of FIG. 2, shown with a side exit port;
[0037] FIG. 10 is a perspective and end view of a tip that can be
used with the catheter of FIG. 2;
[0038] FIG. 11 is a perspective and end view of a tip that can be
used with the catheter of FIG. 2;
[0039] 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;
[0040] 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;
[0041] 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;
[0042] 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;
[0043] FIG. 16 is a schematic view of a focused ultrasound system
that can be used with the system of FIG. 1;
[0044] FIG. 17 is a schematic hardware diagram of a controller of
the system of FIG. 1;
[0045] FIG. 18 is a functional block diagram of the controller of
FIG. 17;
[0046] FIG. 19 is a screen capture of a graphical user interface
that can be implemented by the controller of FIG. 17;
[0047] 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;
[0048] FIG. 20B is a perspective schematic view of the catheter and
patient of FIG. 20A;
[0049] FIG. 20C is a perspective view of the catheter and patient
of FIG. 20A, shown with an infusion port, an injector, and a
controller;
[0050] FIG. 20D is a perspective view of a distal fluid port of the
catheter of FIG. 20A;
[0051] FIG. 20E is a perspective view of a middle or proximal fluid
port of the catheter of FIG. 20A;
[0052] FIG. 21A is a diagram illustrating the controller of the
system of FIG. 1 coordinating control of a pump with a sensed
physiological parameter;
[0053] FIG. 21 B 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;
[0054] 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;
[0055] FIG. 22 is a schematic diagram of a drug delivery system
with a smart lumbar puncture needle;
[0056] FIG. 23 is a schematic diagram of a drug delivery system
with manual pumps;
[0057] FIG. 24A is a schematic view of a drug delivery system;
[0058] FIG. 24B is a perspective view of a needle, hub, and
catheter of the system of FIG. 24A;
[0059] 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;
[0060] 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;
[0061] 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;
[0062] 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;
[0063] 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;
[0064] FIG. 25A is a side view of a catheter tip having a helical
fluid port;
[0065] FIG. 25B is a schematic representation of the geometry of
the helical port of FIG. 25A;
[0066] FIG. 25C is a perspective view of the catheter tip of FIG.
25A;
[0067] FIG. 25D is another perspective view of the catheter tip of
FIG. 25A;
[0068] FIG. 25E is a photograph of an exemplary distribution
pattern achieved using the catheter tip of FIG. 25A;
[0069] FIG. 26 is a schematic diagram of an exemplary method of
using the system of FIG. 24A with a patient;
[0070] FIG. 27 is a schematic diagram of an exemplary method of
patient-specific infusion;
[0071] FIG. 28A is a schematic view of a drug delivery system;
[0072] FIG. 28B is a side view of a tip of a needle of the system
of FIG. 28A;
[0073] FIG. 29 is a sectional side view of a tip of another needle
that can be used with the system of FIG. 28A;
[0074] FIG. 30A is a schematic view of a tip of another needle that
can be used with the system of FIG. 28A;
[0075] FIG. 30B is a schematic view of the needle tip of FIG. 30A
with an inflatable member deployed therefrom;
[0076] FIG. 30C is a schematic view of the needle tip of FIG. 30A
with a fluid being infused through the inflatable member;
[0077] FIG. 31A is a side view of a spinal needle having distal and
radial ports;
[0078] FIG. 31 B is a sectional view of a radial port of the spinal
needle of FIG. 31A;
[0079] FIGS. 31C and 31D are cross-sectional views of the spinal
needle of FIG. 31A;
[0080] FIG. 31 E is a sectional view of a spinal needle having
radial ports;
[0081] FIG. 31 F is a sectional view of another example spinal
needle having distal and radial ports;
[0082] FIG. 32A is a side view of another example spinal needle
having radial ports;
[0083] FIG. 32B is a side view of the spinal needle of FIG.
32A;
[0084] FIG. 32C is a sectional view of the spinal needle of FIG.
32A;
[0085] FIG. 32D is a cross-sectional view of the spinal needle of
FIG. 32A;
[0086] FIG. 32E is a sectional view of another example spinal
needle having distal ports;
[0087] FIG. 33A is a sectional view of a first example connection
for a spinal needle;
[0088] FIG. 33B is a cross-sectional view the spinal needle of FIG.
33A;
[0089] FIG. 33C is a sectional view of a second example connection
for a spinal needle;
[0090] FIG. 34 is a diagrammatic comparison between an exemplary
Pulsar catheter and pump system and a manual bolus injected with a
commercially-available catheter;
[0091] FIG. 35 is a diagrammatic illustration of data from a
pre-clinical study;
[0092] FIGS. 36 and 37 are a schematic view of an example
implantable catheter with an example implantable port;
[0093] FIGS. 38A-38C are schematic views of example catheters;
[0094] FIG. 39A is a side view of an example catheter;
[0095] FIGS. 39B-39D are cross-sectional views of example
catheters;
[0096] FIG. 39E is a side view of an example catheter;
[0097] FIG. 39F is a cross-sectional view of an example
catheter;
[0098] FIG. 39G is a side view of an example catheter;
[0099] FIGS. 39H-39J are cross-sectional views of example
catheters;
[0100] FIG. 39K is a side view of an example catheter;
[0101] FIGS. 39L-39N are cross-sectional views of example
catheters;
[0102] FIGS. 40A-40D are side views of example catheters;
[0103] FIGS. 40E-40I are cross-sectional view of example
catheters;
[0104] FIG. 41A is a top plan view of an example catheter outlet
and tip configuration;
[0105] FIG. 41 B is a sectional perspective view of the catheter
outlet and tip configuration of FIG. 41A;
[0106] FIG. 41C is a sectional view of an example catheter outlet
and tip configuration;
[0107] FIG. 41 D is a sectional view of an example catheter outlet
and tip configuration;
[0108] FIG. 41 E is a sectional view of an example catheter outlet
configuration;
[0109] FIGS. 42A-42C sectional views of example radial ports for a
catheter;
[0110] FIG. 43A is a sectional view of an example arc-shaped
catheter;
[0111] FIG. 43B is a cross-sectional view of the catheter of FIG.
43A;
[0112] FIG. 43C is a cross-sectional view of an example
catheter;
[0113] FIG. 43D is a perspective view of a catheter having example
catheter outlets and ports to disperse material;
[0114] FIG. 43E is a sectional view of a port of the catheter of
FIG. 43D;
[0115] FIGS. 43F and 43H are sectional views of catheters having
example catheter outlets and ports to disperse material;
[0116] FIG. 431 is an illustration of fluid dispensing through a
catheter;
[0117] FIG. 43J is a cross-sectional view of a catheter having an
example port to dispense material;
[0118] FIGS. 44A-44D are sectional views of an example steerable
wire;
[0119] FIG. 45A is a cross-sectional view of an example catheter
having an expandable feature;
[0120] FIG. 45B is a cross-sectional view of an example catheter
having a flexible core;
[0121] FIGS. 45C and 45D are sectional view of the flexible core of
FIG. 45B;
[0122] FIGS. 45E and 45F are sectional views of example
reinforcement layers for a catheter;
[0123] FIG. 46A is a cross-sectional view of an example
catheter;
[0124] FIGS. 46B-46E are sectional views of an example catheter
having a retention device;
[0125] FIGS. 47A-47C sectional vies of example needles for
inserting a catheter;
[0126] FIGS. 48A-48C are schematic views of example tubing set
configurations;
[0127] FIGS. 48D and 48E are schematic views of example extension
lines for a needle or catheter;
[0128] FIG. 49 is a sectional view of an example catheter having a
multi-layer architecture;
[0129] FIGS. 50A and 50B are sectional views of catheters having
example outlets and ports;
[0130] FIG. 50C is a sectional view of a multi-layer composite
catheter;
[0131] FIGS. 51A and 51D are schematic views of an implantable
port
[0132] FIGS. 51 B and 51 E are schematic views of a connector for
the implantable port of FIG. 51A;
[0133] FIG. 51C is a schematic view of the implantable port of FIG.
51A and connector of FIG. 51B;
[0134] FIGS. 52A-52C are schematic views of an example implantable
port and actuator to expand a length of a catheter;
[0135] FIGS. 53A-57B are a schematic views of example retention
features for a catheter;
[0136] FIGS. 58A and 58B are schematic views of an example
expandable catheter;
[0137] FIG. 59 is a sectional view of an example catheter having
features for real-time 3D mapping or positioning;
[0138] FIG. 60A is a side view of an example catheter for blanket
infusion;
[0139] FIG. 60B is a cross-sectional view of the catheter of FIG.
60A;
[0140] FIG. 61A is a side view of an example anchored
guidewire;
[0141] FIG. 61 B is a side view of an example anchored
guidewire;
[0142] FIG. 61C is a side view of the anchored guidewire of FIG.
61B;
[0143] FIG. 61 D is a schematic view of an implanted catheter and
anchored guidewire system;
[0144] FIG. 61 E is a schematic view of an example catheter and
anchored guidewire system;
[0145] FIG. 61 F is a cross-sectional view of the example catheter
and anchored guidewire system of FIG. 61E;
[0146] FIG. 62A is a cross-sectional view of an implanted
catheter;
[0147] FIG. 62B is a cross-sectional view of an example catheter
having longitudinal channels; and
[0148] FIG. 62C is a sectional view of the catheter of FIG.
62B.
DETAILED DESCRIPTION
[0149] 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.
[0150] 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.
[0151] In some embodiments, systems and methods arc 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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 pod
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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] 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.
[0175] 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.
[0176] 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.
[0177] 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.
[0178] 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.
[0179] 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 1208, and a pressure sensor lumen 120C. FIG. 11 illustrates
an exemplary dual-lumen catheter an infusion lumen 120A and an
aspiration lumen 120B.
[0180] 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.
[0181] 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.
[0182] 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 1228 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, 1208 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.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] 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).
[0188] 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.
[0189] 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).
[0190] 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.
[0191] 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.
[0192] 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.
[0193] 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.
[0194] 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.
[0195] 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.
[0196] 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.
[0197] 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.
[0198] 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.
[0199] 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.
[0200] 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.
[0201] 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.
[0202] 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, transcutaneous, 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.
[0203] 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.
[0204] The system 100 illustrated in FIGS. 20A-20E can be used in
acute and/or chronic applications in any of a variety of ways.
[0205] For example, the catheter 102 can be used to deliver three
different drugs (e.g., one drug through each different lumen of the
catheter).
[0206] By way of further example, the catheter 102 can be used for
localized delivery of different drugs to different areas of the
spine.
[0207] As yet another example, the catheter 102 can be used to
deliver the same drug with substantially instantaneous distribution
along the entire spinal column.
[0208] 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.
[0209] 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.
[0210] 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.
[0211] 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.).
[0212] The systems disclosed herein can be used in any of a variety
of drug delivery methods.
[0213] 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 CI 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).
[0214] 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.
[0215] 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.
[0216] 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 con-elation 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.
[0217] 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.
[0218] 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.
[0219] 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).
[0220] 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.).
[0221] 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. 21 B, 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.
[0222] In some embodiments, a dual- or multi-lumen catheter can be
used for alternating, repetitive infusion and aspiration, which can
further enhance drug distribution.
[0223] 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).
[0224] 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.).
[0225] 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.
[0226] 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).
[0227] 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).
[0228] 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.
[0229] 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.
[0230] The following are exemplary drug delivery methods that can
be performed using the systems disclosed herein:
EXAMPLE A
[0231] Alternating Pulsatile infusions of Drug (Pump 1) and
Buffer/Saline (Pump 2)
[0232] Drug Total Volume: 2.2 mL
[0233] Buffer Total Volume: 4.4 mL
[0234] Infusion rate for both pumps: 15 mL/min
[0235] Cycles: 10 cycles at lumbar then 10 cycles at Cisterna
magna
[0236] Time between cycles: 100 milliseconds
[0237] 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
[0238] Alternating Pulsatile infusions of Drug (Pump 1) and
Buffer/Saline (Pump 2)
[0239] Drug Total Volume: 3 mL
[0240] Buffer Total Volume: 20 mL
[0241] Infusion rate for both pumps: 4 mL/min
[0242] Cycles: 13 cycles at thoracic region
[0243] Time between alternating pump 1 to pump 2: 1000
milliseconds
[0244] Time between cycles (pump 2 to pump 1): 5000
milliseconds
[0245] 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
[0246] Alternating Pulsatile infusions of Drug (Pump 1) and
Buffer/Saline (Pump 2)
[0247] Drug Total Volume: 5 mL
[0248] Buffer Total Volume: 8 mL
[0249] Infusion rate for pump 1: 37 mL/min
[0250] Infusion rate for pump 2: 20 mL/min
[0251] Cycles: 5 cycles at thoracic region
[0252] Time between cycles: 10 milliseconds
[0253] 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.
[0254] 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. 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.
[0255] 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.
[0256] 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.
[0257] 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.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] 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.
[0264] 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.
[0265] 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.
[0266] 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.
[0267] 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.
[0268] 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.
[0269] 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.
[0270] The catheter 304 can be formed form any of a variety of
materials. Exemplary materials include polyimide, PEEK,
polyurethane, silicone, and combinations thereof.
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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 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.
[0276] 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.
[0277] 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.
[0278] 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
[0279] 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.
[0280] 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.
[0281] Spinal Needles
[0282] In some embodiments, the delivery device can be or can
include a needle, e.g., a spinal needle. An exemplary spinal needle
can be referred to herein as a "Pulsar Spinal Needle (SN)."
[0283] FIGS. 31A through 33C illustrate an exemplary Pulsar Spinal
Needle 500. A body 501 of the needle 500 can have a gauge in the
range of 7-40 G. The needle 500 can be formed from various
materials, such as stainless steel, titanium, nitinol, rigid
plastic, 3D printable materials and compounds, or combinations
thereof. The needle 500 can include one or more tip outlets 502.
The tip outlet 502 can be a standard outlet, a spiral outlet,
multiple axial holes, multiple axial slits, or other shapes. The
tip outlet 502 can be shaped to enhance dispersion of fluid exiting
the needle. The needle 500 can have one or more outlet holes 504
instead of or in addition to the tip outlet(s) 502. The outlet
holes 504 can be sized, shaped, including circular and oval as
shown, or positioned to generate turbulent, homogeneous axial
infusion with direction, momentum toward a distant target combined
with radial flow to distribute or "fill" around axial stream. The
needle 500 can include a needle hub 506. The needle hub can include
depth markings, markings to indicate orientation of tip outlet 502
or other outlet ports 504, etc. The needle 500 can include a tubing
set 508, e.g., for making fluid connections to a proximal end 510
of the needle 500. The tubing set 508 can include micro-lumen
extrusions 512, e.g., 0.005'' to 0.1'' inside diameter. The tubing
set 508 can include low or zero dead volume luers 514 or other
connectors. The tubing set 508 can include bifurcations with
ergonomic fittings to connect to a plurality of syringes, e.g.,
loaded into a syringe pump. In some embodiments, the tubing set 508
can accommodate 1-10 syringes. The bifurcations can include one or
more valves, which can be configured to prevent or limit mixing of
fluid channels at the bifurcation. The outside of the needle 500,
e.g., an outer surface or outside diameter, can include a coating
or other surface treatment, e.g., to prevent or reduce adhesion of
a drug or other infusate to the needle 500. In some embodiments,
the outside surface of the needle 500 can be coated with PTFE. Such
coatings or treatments can reduce drug adhesion to the needle
surface during infusion in CSF, e.g., to prevent removal of drug
with the needle 500 on retraction of the device. The needle 500 can
be formed as a multi-layer composite. For example, the needle 500
can be a composite rigid needle with layers that include one or
more of a structural layer with a pattern of perforations
alternating with a hydrophilic or nano-porous material layer to
allow localized permeation to CSF and contact tissue in addition to
main fusion stream(s). The needle 500 can be formed as a sandwich
of structural layers (one or both outer surfaces having a pattern
of perforations) with a reservoir disposed between the outer
layers. The reservoir can include hydrophilic or nano-porous
material therein. The needle 500 can include a hydrophilic or
nano-porous layer. The hydrophilic or nano-porous layer can contain
treatment to release on contact with CSF, or the needle 500 can be
soaked to absorb treatment material prior to device insertion. The
needle 500 can include any of the features of other spinal needles
or delivery devices disclosed herein.
[0284] FIG. 31 F illustrates an exemplary spinal needle 500. The
illustrated spinal needle 500 can be referred to as Spinal Needle 1
or "SN1." The needle 500 can include a blunt pencil point 516 22 Ga
needle with 5 holes total: two holes 502 axially aligned on one
side and three additional holes 504 in a ring spaced about the
circumference of the needle 500. The pair of holes 502 can be
inserted aligned "on top" in order to direct flow along the axis of
the spine inside the dura. While the illustrated needle was used
effectively in a sheep model, other designs may require less effort
and be less prone to bending, e.g., by making the tip less blunt.
The needle 500 can include any of the features of other spinal
needles or delivery devices disclosed herein.
[0285] FIG. 32E illustrates another exemplary spinal needle 500.
The illustrated spinal needle 500 can be referred to as Spinal
Needle 2 or "SN2." The needle 500 can include a sharper distal
point 518 than that of SN1. The needle inside surface finish can be
that of commercial needle (to be used as control needle). The fluid
holes 502 of the needle 500 can be located much closer to the
distal tip 518 to minimize leakage and allow for the holes 502 to
be inside the dura in small anatomies. This, plus the relatively
small holes 502 and radiant arrangement can be effective to
minimize leakage. The pair of axially-aligned holes 502 in SN1 can
be replaced with an axially-elongated slot 502' in order to further
concentrate flow toward the cranium/brain. An alignment mark can be
formed on the needle 500, e.g., via laser marking, in alignment
with the slot. A stylet lock alignment feature can also be matched
or aligned with the slot position. The needle 500 can include any
of the features of other spinal needles or delivery devices
disclosed herein.
[0286] FIGS. 33A-33C illustrate two other exemplary spinal needles
500. The needle shown on top can be a dual lumen needle with an
independent middle channel 520 that opens at the tip 516, 518. The
middle channel 520 can be surrounded by another channel 522 that
has multiple side outlets 504, e.g., 2-4, around the perimeter. The
needle 500 shown on the bottom can be a triple lumen needle with an
independent middle channel 520 that opens at the tip 516, 518,
which is surrounded by two other independent channels 522 having
longitudinally staggered side ports 504. The needles 500 can
include any of the features of other spinal needles or delivery
devices disclosed herein.
[0287] Threadable/Steerable Catheters
[0288] In some embodiments, the delivery device can be or can
include a catheter 600, e.g., a threadable and/or steerable
catheter. An exemplary catheter 600 can be referred to herein as a
"Pulsar Threadable/Steerable Catheter (TC/SC)" or "Pulsar
Catheter."
[0289] FIG. 34 illustrates a performance comparison between an
exemplary Pulsar Catheter and an exemplary pump system of the type
described herein (which collectively can be referred to as a Pulsar
Catheter System) and a manual bolus injected with a
commercially-available catheter. As shown, material infused using
the Pulsar Catheter System was successfully spread towards the
cranial space, as compared to the comparison catheter in which
there is leaking backwards towards the lumbar space.
[0290] FIG. 35 illustrates data from a pre-clinical study in which
an exemplary Pulsar Catheter was shown to provide targeted
intrathecal therapy with global bio-distribution as compared to a
manual bolus.
[0291] FIGS. 36 and 37 illustrate an implantable catheter 600 with
an implantable port 602 and a pump 604 with a disposable injection
accessory 606 for interfacing with the port 602. The catheter 600
can be a Pulsar Catheter. Alternatively, a manual syringe or
injector 607 can be used. The catheter 600 can include any of the
features of other catheters or delivery devices disclosed
herein.
[0292] FIG. 37 shows that a catheter 600 can be threaded over a
removable guide wire 608 (guidewire 608 first, catheter 600 over
it), or can be threaded using a stylet (stylet pushes the
catheter). The catheter 600 can be threaded using a guide catheter
(the guide catheter can be threaded first, and the flexible
implantable catheter 600 can then be threaded through the guide
catheter, and then the guide catheter can be removed). The catheter
600 can be threaded using built-in column strength members (e.g.,
wire, coil, braid, etc.) with steering wires 612 (FIGS. 44A-44D) to
navigate the spine or other anatomy. The catheter 600 can be
particularly useful in cases in which spinal fixation or
stabilization is applied to the patient, e.g., using implanted bone
anchors and rods. The catheter 600 can be a Pulsar Catheter. The
catheter 600 can include any of the features of other catheters or
delivery devices disclosed herein.
[0293] FIGS. 38A-38C illustrate an exemplary catheter 600. The
catheter 600 can be a micro-catheter with a body 601 having an OD
of 0.030-0.15''. As shown in FIG. 38A, the catheter 600 can include
multiple lumens 614, e.g., 1-5. The catheter 600 can include
radio-opaque marks 616, e.g., marker bands or prints, for imaging.
The marks 616 can be formed with specific setback lengths from the
tip 618 and/or from side ports or outlets 620. The catheter lumen
614 materials can include Pellethane, fused silica, low-density
polyethylene (LDPE), silicone, polytetrafluoroethylene (PTFE),
expanded polytetrafluoroethylene (ePTFE), polyamide, and/or
combinations thereof. FIG. 38B shows a cross-sectional view of a
multi-lumen catheter 600 with a built-in core wire 622. FIG. 38C
shows a triple lumen catheter 600 layout with various additional
features. The catheter 600 can include a PTFE or other coating of
the OD of the catheter to minimize drug adhesion to the catheter
surface instead of target tissue during infusion in CSF. The
surface coating can also minimize adhesion of drug which might be
removed with the catheter 600 on retraction of the device. The
catheter 600 can include a hub 624 with independent lumen extension
tubing 626 for each lumen 614. The extension tubing 626 can include
connectors 628 to fluidly couple the lumen 614 to other suitable
devices. The catheter 600 can also include a strain relief coating
or cover 630 to protect the coupling between the catheter body 601
and the hub 624. The catheter 600 can be a Pulsar Catheter. The
catheter can include any of the features of other catheters or
delivery devices disclosed herein.
[0294] FIG. 39A-39N illustrate exemplary catheters 600. The
catheter 600 can include crescent or arc-shaped fluid channels or
lumens 632 with unique tip and staggered outlet configurations. For
example, the catheter 600 can include two lumens 614 each with a
distal outlet 634. The lumens 614 can have different lengths so
that the distal outlets 634 are staggered along a length of the
catheter 600. The catheter 600 can have a central lumen 614 coaxial
with an outer lumen 614 or can include a central lumen 614 with up
to four arc-shaped lumens 632. One or more of the lumens 614, 632
can include a manifold tube 636 and one of the lumens 614, 632 can
have a core wire 622 extending within. The arc-shaped lumens 632
can include radial or distal ports 620, 634. The catheter 600 can
include a larger lumen 614 and two smaller lumens 614, one of which
can be dedicated to a core wire 622. In another example, the
catheter 600 can include side-by-side circular and crescent-shaped
lumens 614, 632. In another example, lumens 614 can be co-axial
with one extending around the other. The catheter 600 can include
side or distal ports 620, 634 and markers 616. The catheter 600 can
be a Pulsar Catheter. The catheter can include any of the features
of other catheters or delivery devices disclosed herein.
[0295] FIG. 40A-40I illustrate exemplary catheters 600. The
catheters can include outlets or fluid ports 634 that are staggered
along the length of the catheter 600. The catheter 600 can be a
Pulsar Catheter. The catheter 600 can include any of the features
of other catheters or delivery devices disclosed herein. FIGS. 40E
and 40F illustrates that the outlet configuration can be customized
for specific patients, infusions, diseases, etc. The location of
fluid ports 634 along the length of the catheter 600 can be
adjusted in situ, for example by longitudinally sliding one or more
layers 614 of the catheter 600 relative to one or more other layers
614 of the catheter 600. FIGS. 40G-40I illustrates a multi-lumen
catheter 600 with staggered outlets 634 and a core wire 622.
[0296] FIG. 41A-41E illustrate various catheter outlet/tip
configurations. FIGS. 41A and 41B show a catheter 600 with a spiral
or helical shaped distribution of outlets 634 of three lumens 614
that can help maximize dispersion. One of the outlets 634 can have
a relatively smaller diameter and an expanding, tapered
configuration. FIGS. 41C and 41D show a catheter 600 with a
staggered-bifurcated tip design 638 that can help provide better
bio-distribution at the distal end 618 of the catheter 600. The
catheter 600 can be inserted into the intrathecal space as a
regular tip/staggered port catheter. The catheter end 638 can be
bifurcated once it is in its desired location by rotating or
otherwise actuating a control wire 640 from a proximal end 642.
FIG. 41E shows a catheter 600 with a spiral cut 644 extending
around the tip 618. In one example, a strengthening coil 646 can
extend around the tip 618 between the spiral cut 644. The tip 618
can be formed from polyimide or various other materials. The
catheters 600 can be a Pulsar Catheter. The catheters can include
any of the features of other catheters or delivery devices
disclosed herein.
[0297] FIGS. 42A-42C illustrate a single-lumen catheter 600 having
smaller radial holes 620 at a proximal location and a larger hole
634 at a distal location or at the distal end 618. The smaller
holes 620 can be spaced about the circumference of the catheter
600, e.g., to surround the entire OD of the catheter 600. For
example, the holes 620 can be disposed in axially aligned groups, a
ring around the circumference, or angled or spiraled groups. The
distal/tip opening 634 of the catheter 600 can be effective to bias
flow out of the tip 618 until back pressure forces flow out of the
side holes 620. The side holes 620 can be smaller and/or have a
total cross-sectional area less than the distal tip port 634. This
configuration distributes a flow of therapeutic fluid through the
catheter 600 between the side holes 620 and the distal hole 634.
For example, if the cross-sectional area of the side holes 620 is
equal to the cross-sectional area of the distal hole 634, the flow
equally distributes between the side holes 620 and the distal hole
634. The relative sizes can be configured as desired, e.g.,
30%-70%, 40%-60%, 50%-50%, 60%-40%, 70%-30%, etc. The catheter 600
can include multiple outlet holes 620 along the length with varying
sizes (e.g., from small to large going from proximal to distal) for
infusion along length or at desired locations. The catheter 600 can
be a Pulsar Catheter. The catheter can include any of the features
of other catheters or delivery devices disclosed herein.
[0298] FIGS. 43A-43C illustrate a catheter 600 having a body 648
having a substantially flat or arc-shaped transverse cross-section.
The catheter 600 can facilitate centering, easy push-ability, less
disruption of CSF space 650, and/or less issues with buckling after
implantation. Further, the catheter 600 can include a core wire
622, in a sheath or lumen 650 on a concave side of the body 648,
for example. The catheter 600 can alternatively have an I-beam
structure. The catheter 600 can include staggered outlet ports 634.
The catheter 600 can be a Pulsar Catheter. The catheter 600 can
include any of the features of other catheters or delivery devices
disclosed herein.
[0299] FIGS. 43D-43J illustrate various features that a catheter
600 can include for adding turbulence to disperse infused material
652 and/or enhance circumferential spread of infusate. For example,
the catheter 600 can include a blind end channel 614 or block 653
with side outlets 620, 634. In this example, the infused material
652 impacts the blind end of the lumen 614 and exits the side
outlets 620, 634 in very turbulent flow. As another example, the
catheter 600 can include caged member 654 having side outlets 620.
As another example, the catheter 600 can include a caged member 656
having a 360 degree radial outlet 620. As another example, the
catheter 600 can include a helical or spiral cut 644 in a side
lumen 614 as an outlet to facilitate dispersion and infusion in
arcs, e.g., 270 degree arcs which can provide maximum dispersion in
some embodiments, along with a lumen 614 having an outlet 634 at
the distal end 618. The catheter 600 can be a Pulsar Catheter. The
catheter can include any of the features of other catheters or
delivery devices disclosed herein.
[0300] FIGS. 44A-44D illustrate catheter steering and/or navigation
features. The catheter 600 can include steerable wires 612 having a
tip 658 that can be selectively angled or curved. The steerable
wires 612 can be built-in to the catheter 600. The catheter 600 can
include a bent stylet or guidewire 608 for navigating through
spinal space during threading. The catheter 600 can include a
special tasked lumen 614 that extends from the tip 618 along a
relatively short length of catheter 600 to be used as a dedicated
guidewire lumen. The catheter 600 can be a Pulsar Catheter. The
catheter 600 can include any of the features of other catheters or
delivery devices disclosed herein.
[0301] The catheters 600 herein can include features that allow the
catheter 600 to "grow" or expand over time, e.g., in conjunction
with the growth of a patient in which the catheter is implanted.
FIG. 45A illustrates a catheter 600 having features that allow it
to expand with the patient over time as the patient grows. The
catheter 600 can include an inner layer 660 that incorporates a
standard Pulsar Catheter tip, hybrid design, or other outlet port
configuration disclosed herein to allow for therapeutic infusion.
Multiple lumens 614 can be incorporated. One or more lumens 614 can
be used to run a stylet or guidewire configuration to allow for
increased thread-ability, deflect-ability, and/or steer-ability.
This inner wire 608 can be pre-formed in any of a variety of
beneficial shapes for the above-mentioned characteristics. The
catheter 600 can include another layer 662 that overlaps the inner
layer 660 or inner lumen. The catheter 600 can allow for movement
of the two layers 660, 662 with relation to each other to allow the
overall length of the catheter 600 to increase as axial tension is
applied. An outer layer 664 can cover the entire length of the
catheter 600 to form a seal from the tip 618 and over the multiple
layers 660, 662 that form the expandable sections of the catheter
600. The expandable sections of the catheter 600 can be made of
several layers that allow for axial lengthening. Ports 620, 634 can
be included at various places along the catheter 600 and in the
different layers to allow axial lengthening. The outer sheath 664
can be pre-formed in its shortest length by bunching up 666 the
layer 664 to allow it to be sealed but to expand when pulled
axially. The bunched portion 666 can be aligned with the
overlapping portions of the two layers 660, 662. The outer sheath
664 can be a thin polymer-based layer. The catheter 600 can be a
Pulsar Catheter. The catheter 600 can include any of the features
of other catheters or delivery devices disclosed herein.
[0302] FIGS. 45B-45D illustrate a catheter 600 having a flexible
core 668 with a multi-layer sheath design. The flexible core 668
can have a body or a portion thereof with a flexible or crimped
configuration. The tip 618 can be curved using the flexible core
668. The catheter 600 can be pushed to deflect off of rigid
structures for steering and steerability. The catheter 600 can be a
Pulsar Catheter. The catheter 600 can include any of the features
of other catheters or delivery devices disclosed herein.
[0303] FIGS. 45E and 45F illustrate a catheter reinforcement layer
670 with a braided 672 and/or coiled 674 structure. The structure
672, 674 can improve structural and steerable properties of the
catheter 600. The catheter 600 can be a Pulsar Catheter. The
catheter 600 can include any of the features of other catheters or
delivery devices disclosed herein.
[0304] FIGS. 46A-46E illustrate a catheter 600 having a balloon
676, e.g., at the distal tip 618. The balloon 676 can be used to
retain the catheter 600 in position. The balloon 676 can have a
first inflation state 677 in which the balloon 676 centers the
catheter 600 within a lumen or cavity in which the catheter 600 is
disposed and still allows fluid flow past the balloon 676. For
example, the balloon 676 can have wings 679, such as four as shown,
that can be expanded to establish a diameter without occluding the
lumen or cavity. The balloon 676 can have a second inflation state
678 in which the balloon occludes the lumen or cavity in which the
catheter 600 is disposed, which can be used, e.g., for selective
infusion. The balloon 676 can be inflated or expanded to enlarge
the infusion periphery along the catheter tip 618. This can be
useful, for example, in neonatal or other patients with a very
congested intrathecal space for unrestricted drug infusion. The
catheter 600 can be a Pulsar Catheter. The catheter 600 can include
any of the features of other catheters or delivery devices
disclosed herein.
[0305] FIGS. 47A-47C illustrate a needle 680 that can be used to
insert a catheter. In some embodiments, a Touhy needle can be used
to insert a catheter 600.
[0306] The catheter 600 can include a tubing set 682, e.g., for
making fluid connections to a proximal end 642 of the catheter 600.
FIGS. 48A-48C illustrate exemplary tubing set configurations. The
tubing set 682 can include micro-lumen extrusions 684, e.g.,
0.005'' to 0.1'' inside diameter. The tubing set 682 can include
low or zero dead volume luers or other connectors. The tubing set
682 can include bifurcations 686 with ergonomic fittings to connect
to a plurality of syringes 688, e.g., loaded into a syringe pump.
In some embodiments, the tubing set 682 can accommodate 1-10
syringes 688. The bifurcations 686 can be valve controlled.
[0307] FIG. 48D illustrates an exemplary extension line for a
single lumen needle or catheter.
[0308] FIG. 48E illustrates an exemplary extension line for a
triple lumen needle or catheter.
[0309] FIG. 49 illustrates a catheter 600 having a multi-layer
architecture. The catheter 600 can include multiple fluid lumens
614. The catheter 600 can include any one or more of (1) an inner
liner 690, (2) a braided/coiled layer 692, and (3) a lubricious
outer jacket 694. This construction can improve the thread-ability
and steer-ability of the catheter 600. The catheter body 601 can be
formed from multiple segments with varying stiffness, flexibility,
and/or column strength. The features of each segment can be
controlled by catheter architecture and/or using proprietary
materials. The catheter 600 can be threadable using several
approaches including (1) over a guidewire 608, (2) using
obturators, and/or (3) just by the catheter 600 itself. The
catheter 600 can be a Pulsar Catheter. The catheter 600 can include
any of the features of other catheters or delivery devices
disclosed herein.
[0310] FIGS. 50A-50C illustrate a multi-layer composite catheter
600. The catheter 600 can include a structural layer 700 with a
pattern of perforations 702 alternating with a hydrophilic or
nano-porous material layer 704 to allow localized permeation to CSF
and contact tissue in addition to main infusion stream(s). The
perforations 702 can be any suitable shape, including
parallelepiped, oval, arced, circle, etc. The hydrophilic or
nano-porous layer 704 can contain treatment to release treatment on
contact with CSF, with infusion pressure, or device can be soaked
to absorb treatment material prior to device insertion. The
catheter 600 can include a sandwich of structural layers 700 (one
or both with pattern of perforations 702) with a reservoir 706
disposed between. The reservoir 706 can include a hydrophilic or
nano-porous material therein. The catheter 600 can be a Pulsar
Catheter. The catheter 600 can include any of the features of other
catheters or delivery devices disclosed herein.
[0311] FIGS. 51A-51E illustrate an implantable port 708 that can be
used, for example, to make fluid or other connections with
catheters 600 described herein. The port 708 can include multiple
septums 710 to connect independently to each lumen 614, or to one
port, or all ports. The port 708 can be used with a disposable
injector system. The port 708 can include in-line bacterial
filters. The port 708 can be configured to vibrate or otherwise
move the catheter tip 618 to reduce chances of blockage. The port
708 can include a connector 712 with multiple separate channels 714
(e.g., 3 channels) and needles 716. Alignment between a central
alignment port 718 and an 0-ring 720 can ensure that the connector
712 is positioned properly. Once in place, needles 716 can be
deployed into the septum 710.
[0312] FIGS. 52A-52C illustrate an exemplary implantable and
expandable catheter 600 to account for patient's growth. The length
of the catheter 600 can manually or automatically increase over
time by a degree commensurate with growth of the patient. The
length of the catheter 600 can be rolled around a multi (e.g.,
triple) lumen port 722. During initial implantation, the initial
length (usable length) of the catheter 600 can be set by the
surgeon. As the patient grows, the port 722 can be rotated to
unwind or release a section of the catheter 600 to provide
additional usable catheter length.
[0313] The port 722 can be rotated using an external actuator 724.
The actuator 724 can be magnetic. The actuator 724 can be formed as
an interlocking mechanism to allow the port 722 to be rotated
precisely to the desired catheter length. The port 722 and actuator
724 can have predetermined positions or markings corresponding to
desired units of length to expand the catheter. The catheter 600
can be a Pulsar Catheter. The catheter 600 can include any of the
features of other catheters or delivery devices disclosed
herein.
[0314] Catheters 600 disclosed herein can include anchoring
features 726, e.g., to prevent the catheter 600 from dislodging
once implanted. FIGS. 53A and 53B illustrate a catheter 600 having
a balloon 676 that can be inflated or expanded to anchor the
catheter 600 and/or to allow for target occlusion for focal
infusion. The catheter 600 can be a Pulsar Catheter. The catheter
600 can include any of the features of other catheters or delivery
devices disclosed herein. FIGS. 53C-53E illustrate a catheter 600
with inflatable or expandable balloons 676 that can be used occlude
an intrathecal space or other area/cavity. The balloons 676 can be
placed distally, i.e., at the distal tip 618, or proximally, i.e.,
at the proximal end 642, to occlude flow in either direction. The
distal only balloon 676 can be inflated to control or limit flow in
the proximal direction. The proximal only balloon 676 can be
inflated to control or limit flow in the distal direction. Both
balloons 676 can be inflated at the same time to control or limit
flow only between the balloons 676 or to hold the therapeutic in
the designated location. Multiple ports 620, 634 can be used to
administer therapeutic distal of the distal balloon 676, proximal
of the distal balloon 676, distal of the proximal balloon 676,
proximal to the proximal balloon 676, or any combination thereof.
More than one or two balloons 676 can be utilized in the same
manner to control location of flow, isolation, or therapeutic
combinations thereof, e.g., for up to as many therapeutic lumens as
there are incorporated in the catheter 600. The distal balloon 676
can be retractable into the inner lumen 614 of the catheter tip 618
during threading, steering, introducing or at different times the
use of the balloon 676 would be beneficial to the delivery of the
therapeutic. The proximal balloon 676 can be fixed into the wall
694 of the catheter 600 or can be located on an outer sheath that
allows its location to slide distally or proximally to position the
balloon 676 for use. The balloon 676 can be positioned in different
locations forward or rearward of ports 620, 634 to activate or
deactivate access to defined ports 620, 634. The number of ports
620, 634 can be up to all lumens 614 needed or defined for the
catheter 600 to carry therapeutic. The catheter 600 can be a Pulsar
Catheter. The catheter 600 can include any of the features of other
catheters or delivery devices disclosed herein.
[0315] FIG. 54 illustrates a catheter 600 having a deployable
feature for anchoring the catheter 600, or the tip 618 thereof. The
feature 726 can be deployed to anchor the catheter 600 at the tip
618 or at other locations along the length of the catheter 600. A
preformed nitinol or shape-memory wire 728 can be retracted into an
inner lumen 614 of the catheter 600 during insertion, threading, or
other required steps of the acute procedure. Once it is desired
that the catheter 600 be anchored, the nitinol wire 728 can be
extended to allow it to take its preformed shape and anchor the
catheter 600 with outwardly extending portions 730. The nitinol
wire 728 can be a single wire of many different shapes beneficial
to have the desired effect of anchoring, or a double wire to
increase its expandable reach in two or more directions. This
anchoring feature 726 can be used in multiples along the length of
the catheter 600 to increase its anchoring effect. The nitinol wire
728 can be shaped to be atraumatic and can be of different
diameters for optimal properties of flexibility and stiffness. The
preformed wire 728 can have several different bends in it and in
different directions. The nitinol wire 728 can also be used for
deflect-ability, steer-ability, or to change the location of bend
or stiffness of the catheter 600 for placement or threading
benefits or characteristics. The catheter 600 can be a Pulsar
Catheter. The catheter 600 can include any of the features of other
catheters or delivery devices disclosed herein.
[0316] FIGS. 55A-55G illustrate a catheter 600 similar to that
shown in FIG. 54. The nitinol or shape-memory wire 728 can be
formed into a spiral/helix 732, or corkscrew 734 shape to allow it
to be deployed in a circular motion to anchor into tissue. The wire
728 can be deployed at the distal tip 618 or proximally along the
length of the catheter 600. The catheter 600 can be a Pulsar
Catheter. The catheter 600 can include any of the features of other
catheters or delivery devices disclosed herein.
[0317] FIGS. 56A-56D illustrate a catheter 600 having anchoring
features 726 extending therefrom. The anchoring features 726 can
includes hairs or spindles 736 that extend from the catheter to
anchor the catheter to the dura when threaded. The spindles can be
flexible enough to remove the catheter if enough axial force is
provided. The catheter can be a Pulsar Catheter. The catheter can
include any of the features of other catheters or delivery devices
disclosed herein.
[0318] FIGS. 57A and 57B illustrate a catheter 600 having an
anchoring feature 726 in the form of a suture 738, tab 740, or
anchor. The anchoring feature 726 can be deployed from the catheter
600 to anchor it in place, e.g., to the dura 742. This can prevent
or limit migration, e.g., allowing the catheter 600 to stay in
place when the patient moves. Since the catheter 600 is anchored,
the extra length of the catheter 600 can be coiled and pulled as
the distal end 618 of the catheter 600 moves with height increase
of the patient. The catheter 600 can be a Pulsar Catheter. The
catheter 600 can include any of the features of other catheters or
delivery devices disclosed herein.
[0319] FIGS. 58A and 58B illustrate a catheter 600 configured to
expand to account for a patient's growth. The catheter 600 can
include retractable distal anchor clips, splines, and/or hooks. The
catheter 600 can be selectively expanded by stretching a
helical-cut portion 744 of the body 601. The catheter can include a
magnetic "anchor" device. The anchor can be under the patient's
skin or on the patient's skin, e.g., in the manner of a port on the
device. The catheter 600 can be a Pulsar Catheter. The catheter 600
can include any of the features of other catheters or delivery
devices disclosed herein.
[0320] FIG. 59 illustrates a catheter 600 having features for
real-time 3D mapping or catheter positioning. For example, the
catheter 600 can include passive electrode rings 746 wired to a
junction box for a mapping system. A map can be generated from an
MRI, catheter sweeps, or other accessories. The catheter 600 can be
a Pulsar Catheter. The catheter 600 can include any of the features
of other catheters or delivery devices disclosed herein.
[0321] FIGS. 60A and 60B illustrate a catheter 600 and associated
method of blanket infusion in which the catheter 600 is retracted
while infusing. Specifically, a first step can be used to infuse
for cervical/brain (intracranial) delivery and then a second step
can include radial infusion while the catheter 600 is retracted
from the space to delivery an intrathecal "blanket" infusion. For
example, the catheter 600 can be configured with a central lumen
614 having an outlet 634 at the distal tip 618 and arc-shaped
lumens 632 can be distributed around the central lumen 614. Each of
the arc-shaped lumens 632 can include one or more radial ports 620,
634. The catheter 600 can be a Pulsar Catheter. The catheter 600
can include any of the features of other catheters or delivery
devices disclosed herein.
[0322] FIGS. 61A and 61C illustrate a catheter 600 with an
extendable anchored guidewire 608 for single infusion or long-term
use. The guidewire 608 can include an extension portion 748 having
an outwardly extending shape, such as helical as shown, to anchor
the guidewire 608 with minimal flow resistance or anatomical
trauma. The catheter can be a Pulsar Catheter. The catheter can
include any of the features of other catheters or delivery devices
disclosed herein.
[0323] FIGS. 61 D-61F illustrate a catheter 600 and anchored guide
("guide wire") system 750 including a guide 752 with an anchor 752.
In some embodiments, the system 750 can help ensure ideal catheter
tip 618 positioning for infusion, e.g., closest to the brain, with
least obstruction to infusion flow, while leaving all infusion
lumens 614, ports 634, 620, etc. patent for infusion and without
increasing the catheter diameter. The guide 752 and catheter 600
may be implanted for long term infusion, may be introduced for a
single procedure, or the guide 752 may be left implanted for
multiple, efficient catheter exchanges/introductions for infusion
treatment. The guide 752 and anchor 754 can be placed by use of an
appropriate micro catheter. The anchor 754 can be in the form of a
helix to create an open infusion space by "tenting" the dura away
from the spinal cord for enhanced tip infusion toward the brain.
The entire guide/anchor 752, 754 or a portion thereof can have a
surface coating for functionality: lubricity, treatment, and
implantation compatibility. The guide 752 may have a physical
"stop" feature 756 adjacent to the shaped anchor feature 754 to
assure optimal catheter 600 position, and assure catheter 600
doesn't interfere with (collapse or move) the anchor feature 754.
The "stop" feature 756 may be a link, crimp, splice, or bond of
anchor feature 754 to the guide body a very "trackable," compliant,
"pliable" guide body length. For guide implanted use (no catheter),
an exemplary compliant guide material may have a loop of guide
placed in the lower lumbar region to allow for patient growth. For
implanted use of the guide 752 alone, or implant of guide 752 with
catheter, the guide 752 can anchor in a specially designed port
758. Where the guide 752 is to be implanted and the catheter 600 is
to be introduced, the guide 752 can be released from the port 758,
slack length can be pulled taut, and the guide 752 can be extended
by mechanically attaching a desired extension length for catheter
600 introduction. For exchange of catheters 600, or for patient
growth, the guide 752 can be extended by mechanically attaching a
selected length of guide 752 for temporary or permanent use. The
port 758 can include a catheter anchor connection, infusion
septums, guide anchoring, and/or provisions for catheter/guide
removal, adjustment, or exchange. The guide anchor and body
materials can include, for example: super flexible, strong fine
metal wire, polymer monofilament or multi filaments: Nitinol
(shaped anchor, straight body), Inconel, Monel, Hastalloy, Dacron,
PEEK, LCP, special high strength PE, nylon, and so forth.
[0324] Multi-port intrathecal catheter designs have been described
in the literature and continue to be developed for their design
advantages for infusion coverage and reach. Some uses for catheter
designs having ports located along the catheter in addition to the
catheter tip rely on flow outside the catheter in the intrathecal
space. The catheter shown in FIGS. 62B-62C can potentially advance
performance of multiple port threadable intrathecal catheters,
particularly when used in confined anatomy. During a recent sheep
animal study using threadable catheters, it was observed that the
anatomy (subarachnoid space) can be sufficiently small such that
the catheter may be in contact with both the spinal cord and the
dura, which can essentially elastically seal on the catheter length
and form a tent, leaving only two small triangular interstitial
openings in the subarachnoid space remaining for axial infusion.
This essentially isolates each port infusion to a degree. FIG. 62A
schematically illustrates this "constrained catheter infusion"
phenomenon, as adapted from fluoroscopic infusion study
observations.
[0325] In this case, a smooth round crescent lumen multi-lumen
extruded tube catheter having 0.042'' OD was used in a sheep to
infuse an omnipaque solution in the intrathecal space and follow
the contrast with normal saline "chaser." With one fluoroscopic
view there was a thin, high contrast line on one side of the device
(due to additive effect of superimposed lines of contrast media
flow), whereas the fluoroscopic angle 90 degrees from that view
produced a wider, lower contrast flow image.
[0326] FIG. 62B illustrates an exemplary "channeled" catheter 600
having a surface design to minimize contact surface constraint of
infusion flow. The catheter 600 can include longitudinal channels
760 on the exposed surface 762 of the catheter 600 to create flow
channels in spite of tissue contact in order to facilitate infusion
flow along the catheter 600 even when in contact with the elastic
dura, spinal cord, or other anatomy. The catheter 600 can be formed
by extrusion. The catheter can have closely set, relatively tall
radial ribs 764, or splines. The space between these protrusions
764 can form a flow channel 760. The separation of these features
can be kept low to prevent tissue sagging in, blocking, or entering
the channel.
[0327] The catheter 600 can be splined or channeled along some or
all of the catheter length. The illustrated arrangement shows
splines 764 on the exposed "stagger" length of the catheter shaft,
e.g., the length of the catheter along which multiple ports 620,
634 are longitudinally spaced. The actual dimensions and
proportions can be changed to balance various design requirements
including flow channel capacity and tissue spanning of channels
760. Narrow, relatively deep channels 760 can be advantageous, as
they can remain open and the number of channels 760 can be
relatively high. The spline extrusion ID can be the lumen 614 for
the tip port 634, which can also serve as an over-the-wire
guidewire lumen. This spline tube can be exposed within the stagger
length (tip port 634-to-side port 620). The spline tube can nest
within a proximal outer tube 766. The spline channels 760 can be
used as stagger port lumens as well. The second, outer tube 766,
having a smooth inner and/or outer surface, can attach to or cover
the spline tube. As shown in FIG. 62C, the open end of this outer
tube 766 can become the "stagger port." The catheter 600 can be a
Pulsar Catheter. The catheter 600 can include any of the features
of other catheters or delivery devices disclosed herein.
[0328] Additional Features
[0329] Any of a variety of additional features can be included or
incorporated in the delivery devices disclosed herein, including
the various catheters and needles. The device can include sensors,
which can be connected to a pump or external devices. A pressure
sensor can be used to measure CSF pressure, e.g., to calibrate the
pump for CSF pulsatility, and/or to measure max CSF pressure during
infusion for safety. Other sensors can be used to measure drug
concentration, biomarkers, and the like. The device can include a
micro-camera and light source.
[0330] The devices disclosed herein can be used in any of a variety
of methods. In some embodiments, a convection-dispersion method can
be used in which the drug is followed by saline, or the patient's
own aspirated CSF, or artificial CSF, or drug buffer, or another
biocompatible fluid, to convectively displace and disperse the drug
and enhance biodistribution in the CSF space including the
cranium.
[0331] In some embodiments, alternate small pulsatile infusions of
drug and another fluid can be used. This can include aspiration of
CSF, followed by pulsatile/constant infusion of drug and another
fluid.
[0332] In some embodiments, a small amount of another fluid can be
infused first, followed by drug.
[0333] In some embodiments, a small amount of another fluid can be
infused, then drug, then again followed by another fluid.
[0334] In some embodiments, a small amount of another fluid can be
infused, then drug and another fluid in alternate pulses.
[0335] After infusion, the CSF space can be pulsed (by withdrawing
and infusing CSF, e.g., 0.1-1 mL of CSF, net 0 mL) to generate
micro-pulsatility in the CSF space to enhance interstitial space
and other small-space drug uptake.
[0336] A number of methods can be particularly useful for
threadable catheters including any one or more of: (i) simultaneous
aspiration and infusion-aspiration of CSF from distal tip and
infusion of the drug from staggered outlet to enhance drug
distribution in intrathecal space; (ii) infuse drug and another
fluid from distal tip to push into the cisterna and cranial space;
(iii) infuse drug from distal tip, and another fluid from staggered
outlet; (iv) aspirate CSF from tip prior to any infusion; (v)
aspirate CSF from the tip port synchronous with infusion from one
or a sequence of staggered outlet(s) to convey drug towards tip,
ceasing aspiration at a specific volume of infusion to prevent
aspiration of drug, continuing infusion from staggered port and/or
a distal port at or near the tip; (vi) infuse a CSF compatible
fluid, within safe limits, prior to infusion of any of these
methods in order to create space for accelerated infusion flow;
(vii) aspiration from Touhy needle after infusion to normalize
ICP/CSF pressure; (viii) infuse drug from one outlet and aspirate
CSF from another staggered outlet to convect drug towards staggered
outlet; (ix) recirculate drug between staggered ports to keep drug
distribution localized between the ports; and (x) infuse, aspirate
between the Tuohy outlet and catheter outlets, including the
synchronous tip aspiration/(needle) infusion.
[0337] The systems herein can connect to a sensor or a vest worn by
a patient, where the vest can compress/decompress timed with the
pulsatile infusions to enhance spread of drug in CSF space.
[0338] The systems herein can connect to a light-guide that
switches colors to instruct the patient to breathe with the light,
and the infusion pulses can be timed to the light for controlled
and enhanced spread.
[0339] Priming methods for the systems herein can include
pre-washing the lumen with saline, buffer, CSF, artificial CSF,
HAS, or other fluid to prevent drug particle sticking.
[0340] Priming methods for the systems herein can include pre-fill
and soaking lumen with drug to coat the lumen to prevent additional
drug particle sticking.
[0341] The systems herein can allow introduction and infusion of
in-line-air in a controlled manner at the end of the infusion to
minimize drug dead volume.
[0342] The systems herein can include an implantable catheter
and/or a pump. The catheter can be a valved catheter of the type
described herein. The pump can be a constant flow or micro-dosing
programmable implantable, programmable and refillable (optional)
pump. The catheter can include a flow and/or pressure sensor at the
distal end of the catheter to detect catheter displacement and/or
blockage. The pump can be an implantable chambered pump with double
or single reservoir (one reservoir containing drug and one
containing another fluid such as artificial CSF or drug buffer)
attached to the catheter. Infusion through the catheter can include
(i) slowly continuously through one lumen/outlet, multiple
lumens/outlet, or same lumen/multiple staggered sized outlets; (ii)
pulsatile infusions; (iii) consecutive infusion of drug and drug
buffer; and/or (iv) infuse/aspirate to create pulsation, with net
positive infusion.
[0343] The systems herein can be used to pulse the CSF space (by
withdrawing and infusing small volumes) to generate
micro-pulsatility in the CSF space to enhance interstitial space
and other small-space drug uptake.
[0344] The systems herein can include an implanted pump connected
to a computer (via wireless-architecture or otherwise) to monitor
real-time drug infusion/pressure data. A drop in the infusion rate,
increase in pressure, or other detected parameter can trigger an
alert to be sent to a care-giver or user.
[0345] The systems and methods herein can be used to treat any of a
variety of conditions or diseases, including Parkinson's,
Friedreich's Ataxia, Canavan's disease, ALS, Congenital Seizures,
Drevets Syndrome, pain, SMA, Tauopathies, Huntington's,
Brain/Spine/CNS tumors, inflammation, Hunters, Alzheimer's,
hydrocephalus (therapeutic cure for hydrocephalus), Sanfillippa A,
B, Epilepsy, Epilepsy pre-visualase, PCNSL, PPMS, Acute
disseminated encephalomyelitis, Rx of motor fluctuations in
advanced Parkinson's patients, Acute repetitive seizures, Status
epilepticus, ERT, and/or Neoplastic meningitis.
[0346] The systems and methods herein can be used to deliver any of
a variety of drugs, including antisense oligonulceotides, Adeno
Viruses, Gene therapy (AAVs and non-AAV) including gene editing and
gene switching, Oncolytic immunotherapies, monoclonal and
polyclonal antibodies, stereopure nucleic acids, small molecules,
methotrexate, Edavaronc-conjugate, Conotoxin, abomorphinc,
Prednisolone hemisuccinate sodium, Carbidopa/Levodopa,
tetrabenazine, BZD (Diazepam and Midazolam), Alphaxalone or other
derivative, Cyclophosphamide, Idursulfase (Elaprase), Iduronidase
(Aldurazyme), Topotecan, and/or Buslfan.
[0347] Auto-Injector Syringe Pump
[0348] The systems herein can provide a customized drug delivery
platform to address the unmet need of delivering drugs
intrathecally and beyond. This can be particularly useful for CNS
as the presence of the blood brain barrier (BBB) is a major
impediment for drug delivery to the Central Nervous System (CNS).
The most practical way of delivering drug to CNS by circumventing
the BBB is through the intrathecal space. However, current manual
intrathecal delivery techniques are sub-optimal, and not suited for
the delivery of therapeutics. The systems herein can provide
improved controlled and repeatable bio-distribution and spread of
the therapeutic in the CNS space. An exemplary system can include a
programmable multi-syringe pump with custom algorithm, which can
provide controlled intrathecal delivery of therapeutics.
[0349] An exemplary system can include any one or more of the
following features:
[0350] Drive and operating condition: (i) triple drive system
syringe pump with independent control; (ii) each drive can
communicate with each other; (iii) each syringe can be operated
independently with independent pusher block; each drive can be
programmed, e.g., using a laptop or other computer system via
RS-232 or other connection.
[0351] Pump function: programmable with infusion/withdraw
capability for each drive, in programmed sequences such as (i)
bolus mode; (ii) pulsatile mode, (iii) ramp mode, (iv) variable
flowrate mode; (v) target volume; (vi) target time; (vii)
functional variables such as flow rate, volumes, vary # of cycles,
vary time delay between cycles, sync cycles to pressure sensor
input.
[0352] Software: integrated programmable software for (i)
programming the operational parameters and steps in the pump
display and external computer system or laptop; (ii) communication
between multiple (e.g., three) drives; (iii) capability to interact
with in-line pressure sensors.
[0353] Clamping System: the pump can include an automated clamping
system to clamp tubing set at pre-programmed times. The clamping
system can clamp and unclamp multiple extension lines. The clamping
system can clamp based on infusion profile setting or with separate
program. The clamping system can include clearly identified ports
for lumens and extension lines.
[0354] Sensor: the pump can communicate with built-in/in-line
sensor such as a pressure sensor, 1CP sensor, etc.
[0355] Non-Volatile Memory: settings, drug dose Profiles, syringe
profiles (including custom inputs), acceptable force limit for
different syringe types, and/or various other data can be stored in
the system, including on non-volatile memory.
[0356] Alarm: the system can provide audible, visual, tactile, or
other alarms based on flow rate, pressure, bubbles, empty syringe,
emergency stop, high ICP pressure, high in-line pressures, etc.
[0357] Ergonomics: the system can have a compact design, be
portable, have smooth edges and features, and custom artwork and
colors.
[0358] The drives of the pump system can have any one or more of
the following specifications:
[0359] Pump Operational Accuracy: .+-.0.25%
[0360] Flow accuracy of the pump: .+-.2%
[0361] Reproducibility: .+-.0.05%
[0362] Syringe compatibility: 250 .mu.l to 50 ml
[0363] Minimum Flow Rate: 1 .mu.l/min
[0364] Maximum Flow Rate: 100 ml/min
[0365] Display: Yes
[0366] Non-Volatile Memory: Yes (to store all settings)
[0367] Connectors: USB; RS-485; RS-232
[0368] Linear Force (Max 100% Force): 75 lbs (adjustable force)
[0369] Driver Motor: 0.9 degree stepper motor control (equivalent
to 400 step/rev) or 1.8 degree stepper motor control (equivalent to
200 step/rev).
[0370] Motor Drive Control: microprocessor with 1/32 microstepping
or 1/16 microstepping
[0371] Minimum Pusher Travel Rate: .about.0.24 mm/min (assuming
scale length of 250 .mu.l syringe=60 mm and 50 ml syringe=81
mm)
[0372] Maximum Pusher Travel Rate: .about.51 mm/min (assuming scale
length of 250 .mu.l syringe=60 mm and 50 ml syringe=81 mm)
[0373] AC/DC Adapter: Standard
[0374] Stall Detection: Two independent stall detection
[0375] Pump System
[0376] The systems herein can include a pump system. The pump
system can be configured to hold 1-10 injectable drug vials or
injection syringes, each operated independently on a separate drive
or via synchronous drives. The pump system can use independent
syringes or a same syringe for CSF aspiration and infusion. An
infusion profile can be customized manually or remotely based on
clinical infusion protocols. Remote control (cabled hand module or
local wireless) capability can range from start/stop, monitoring,
or program/parameter settings. Infusion/aspiration program/profiles
can be pre-planned, stored on media for reference, or use. The pump
can incorporate patient or environmental monitored parameters to
integrate for display, feedback, and/or as data for algorithm input
for infusion/aspiration control.
[0377] The system can include customizable software with
programmable manual or via secure cloud algorithm for
infusions/aspirations per drug protocol. The system can be
programmable based on need to increase concentration of the drug to
the Targets of Interest (TOIs). The software can be configured to
concurrently infuse and aspirate at the same time with same or
varying flow rates. The software can allow selectable, concurrent
or sequencing of syringes to infuse/aspirate from various device
port locations. The software can allow selection of volumes,
flowrates, aspirate and infuse, different modes of
infusion/aspiration profile such as constant rate infusion,
pulsatile infusion, step-ramp infusion, timing of aspiration and
infusion delays, etc.
[0378] Drug infusion protocol data can be input into the pump
system. The data can be input manually or remotely (e.g., via
secure cloud), can be USB pre-programmed, can be input from some
other type of hard-drive/hardwire, can be downloaded from the
cloud, etc.
[0379] The system can store infusion and patient data in a cloud.
The system can be compact to be bedside. The system can be MR
compatible. The system can include respiration per minute (RPM)
inputs, respiratory diaphragm movement inputs, electrical inputs
for patient ECG, respiration, CSF pressure, arterial/venous
pressure or other physiological parameters. The system can time
infusions in small pulses (e.g., 0.1-1.0 mL each) with these
patient variables to spread the drug in desired profile.
[0380] The system can connect to one or more wearable sensors
placed or worn by the patient, e.g., in an article of clothing such
as a vest, where the sensor or vest can compress/decompress timed
with the pulsatile infusions to enhance spread of drug in CSF
space.
[0381] The system can connect to a light-guide that switches colors
to instruct the patient to breathe with the light, and the infusion
pulses can be timed to the light for controlled maximum spread.
[0382] The system can connect to in-line pressure measurement
system during prescribed infusions over time and analyze the
pressure data to dictate the pump for emergency stop.
[0383] The system can include wireless connection capability to
computers and sensors to monitor different conditions of the
patient. The system can be configured to provide automated delivery
of secondary infusion when necessary or desirable. The system can
be configured for remote calibration capacity for dose accuracy.
Dose data can be sent to a secondary computing software to monitor
the infusion profile vs. the delivered dose in real-time to ensure
dose accuracy. The system can be configured such that pump infusion
data can be accessed anytime from any computer to get access to
patient infusion information and pump data management. The system
can include an automated priming feature that detects and
eliminates in-line air. Priming vials can be selected separately
and the pump can use the fluid from that vial to prime the
connected lines until no air is present in the system. The system
can be configured to introduce and infuse in-line-air in a
controlled manner at the end of the infusion to minimize drug dead
volume.
[0384] A drug delivery system is disclosed that 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.
[0385] The system can include one or more of: the controller
synchronizes infusion frequency with a frequency of a patient's
natural intrathecal pulsation as measured by the sensor; the
controller synchronizes infusion phase with a phase of a patient's
natural intrathecal pulsation as measured by the sensor; the
controller establishes a sinusoidal approximation of the patient's
natural intrathecal pulsation as measured by the sensor and
synchronizes infusions with the ascending wave of the sinusoidal
approximation; the controller establishes a sinusoidal
approximation of the patient's natural intrathecal pulsation as
measured by the sensor and synchronizes infusions with the
descending wave of the sinusoidal approximation; the sensor is
configured to measure intrathecal pressure; the sensor comprises a
first sensor configured to measure intrathecal pressure and a
second sensor configured to measure heart rate, and the controller
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; further including an implantable infusion
port in fluid communication with the catheter and an extracorporeal
injector configured to mate with the infusion port; the catheter
comprises first and second fluid lumens, and wherein the controller
is configured to control the pump to alternately aspirate fluid
through the first fluid lumen and infuse fluid through the second
fluid lumen in coordination with the physiological parameter
measured by the sensor; or the sensor is configured to measure at
least one of heart rate. intrathecal pressure, intrathecal
pulsation rate, respiration rate, lung capacity, chest expansion,
chest contraction, intrathoracic pressure, and intraandominal
pressure.
[0386] A method of delivering a drug to a patient is disclosed that
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.
[0387] The method can include one or more of: synchronizing
infusion frequency with a frequency of the patient's natural
intrathecal pulsation as measured by the sensor; synchronizing
infusion phase with a phase of the patient's natural intrathecal
pulsation as measured by the sensor; 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; 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
is configured to measure intrathecal pressure; the sensor comprises
a first sensor configured to measure intrathecal pressure and a
second sensor configured to measure heart rate; establishing a
correlation between heart rate and intrathecal pressure based on
the 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 comprises first and
second fluid lumens, and wherein the method includes controlling
the pump to alternately aspirate fluid through the first fluid
lumen and infuse fluid through the second fluid lumen in
coordination with the physiological parameter measured by the
sensor; the sensor is configured to measure at least one of heart
rate, intrathecal pressure, intrathecal pulsation rate, respiration
rate, lung capacity, chest expansion, chest contraction,
intrathoracic pressure, and intraabdominal pressure; the catheter
is 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; delivering a plurality of different drugs through
the catheter, each of the drugs being delivered through a
respective fluid lumen of the catheter; with the controller,
controlling the pump to aspirate fluid through the catheter; the
catheter includes a plurality of outlet ports spaced in a
cranial-caudal direction along the length of the catheter and
wherein the method includes 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
is 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; 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;
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 comprises about 10% by volume of the
patient's total CSF; the catheter is inserted through a
percutaneous lumbar puncture in the patient; the infusion comprises
alternating between infusing a first volume of the drug and
aspirating a second volume of the drug, the second volume being
less than the first volume; the drug is delivered to a target
region, the target region being at least one of an intrathecal
space of the patient, a 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 includes 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
includes 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; determining a total CSF volume
of the patient and tailoring the infusion based on the total CSF
volume.
[0388] A method of delivering a drug to a patient is disclosed that
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.
[0389] The method can include one or more of: the infusion
overrides the natural CSF pulsation of the patient to urge the drug
towards the target site; the infusion coordinates with the natural
CSF pulsation of the patient to urge the drug towards the target
site; the infusion comprises 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 comprises 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 is
disposed in the target region; at least one of the infusion and the
aspiration is coordinated with a physiological parameter of the
patient; the physiological parameter is 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 comprises first
and second fluid lumens, and wherein the method includes
controlling the pump to alternately aspirate fluid through the
first fluid lumen and infuse fluid through the second fluid lumen;
the catheter is 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; 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; alternating between
infusing a first volume of the drug and aspirating a second volume
of the drug, the second volume being less than the first volume;
the target site is at least one of an intrathecal space of the
patient, a 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
includes at least one of an antisense oligonucleotide, a stereopure
nucleic acid, a virus, adeno-associated virus (AAV), non-viral gene
therapy, vexosomes, and liposomes; 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;
determining a total CSF volume of the patient and tailoring the
infusion and/or the aspiration based on the total CSF volume.
[0390] A drug delivery catheter is disclosed that 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 huh to a proximal end of the tip.
[0391] The device can include one or more of: the tip has a tapered
distal end; the first and second fluid ports are offset from a
central longitudinal axis of the tip; at least one of the first and
second fluid ports is aimed perpendicular to, or at an oblique
angle with respect to, the central longitudinal axis of the tip;
the first and second fluid tubes extend uninterrupted through the
hub; the first and second fluid tubes terminate within the hub at
respective connectors to which proximal extension tubes can be
selectively coupled; the guidewire extends uninterrupted through
the hub; the first and second fluid tubes have respective fluid
connectors at proximal ends thereof; at least one of the first and
second fluid tubes is formed from fused silica; at least one of the
first and second fluid tubes is coated in shrink tubing; the sheath
is formed form polyurethane; the sheath includes 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 has a helical interior; at least one of the first and
second ports has an interior that tapers towards the distal end of
the port; the first fluid port is proximal to the second fluid
port; an auger rotatably mounted within the catheter; a
piezoelectric transducer disposed within the catheter.
[0392] A percutaneous needle device is disclosed that 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.
[0393] 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.
[0394] A catheter is disclosed that includes an elongate body
having one or more fluid lumens formed therein; a fluid port formed
in the catheter, the fluid port being defined by a helical slit
formed in a wall of the catheter.
[0395] The catheter can include one or more of: an atraumatic
distal tip defined by a substantially spherical bulb; the catheter
includes a second, distal-facing fluid port; the helical slit is
formed in a sidewall of a reduced-diameter portion of the catheter;
the catheter includes a tapered transition between a main body of
the catheter and a reduced-diameter portion of the catheter.
[0396] A patient-specific infusion method is disclosed that
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.
[0397] The method can include one or more of: 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 is determined from a pre-operative image of the patient's
central nervous system; the aspirated volume of CSF is in the range
of about 1% to about 20% of the total CSF volume of the patient;
the drug is infused while the volume of CSF is aspirated.
[0398] A drug delivery system is disclosed that includes an
intrathecal catheter or needle having at least one fluid lumen; and
a pump configured to infuse fluid through the catheter according to
a programmed infusion profile. The pump can include a plurality of
syringes.
[0399] A method is disclosed that includes inserting a catheter
into an intrathecal space of a patient, the catheter being
configured to increase in length with growth of the patient.
[0400] The method can include one or more of: excess lumen of the
catheter is initially implanted with a port and, as the patient
grows, the catheter can be manipulated to extend in length with
patient growth; or a distal anchoring mechanism to enable axial
tension for catheter to increase in length with patient growth.
[0401] A method of applying targeted infusions to lumbar, thoracic,
and cervical regions of the spine as well as the brain is
disclosed. The method of can include using an infusion profile that
targets specific areas of the intrathecal space and mechanism to
assist in targeting
[0402] A method of anchoring a catheter within a spinal column of a
patient as to avoid migration of catheter while implanted is
disclosed.
[0403] A method of easily implanting a catheter from the lumbar
region to the cervical region of a patient is disclosed. The method
can include a catheter configured for such easy implantation.
[0404] A needle configured for maximum dispersion during injection
is disclosed. The needle can include multiple lumens to allow drug
and buffer infusions, simultaneously or independently.
[0405] 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; U.S. Application Ser. No. 15/151,585, filed on May
11, 2016; and U.S. Application Ser. No. 15/662,416, filed on Jul.
28, 2017; are all hereby incorporated herein by reference in their
entirety.
[0406] 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.
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