U.S. patent application number 17/236446 was filed with the patent office on 2021-08-05 for atraumatic occlusive system with compartment for measurement of vascular pressure change.
This patent application is currently assigned to Surefire Medical, Inc.. The applicant listed for this patent is Surefire Medical, Inc.. Invention is credited to Aravind Arepally, David Benjamin Jaroch, Patrick Charles McCain, Erik Dean Olson.
Application Number | 20210236135 17/236446 |
Document ID | / |
Family ID | 1000005534752 |
Filed Date | 2021-08-05 |
United States Patent
Application |
20210236135 |
Kind Code |
A1 |
Olson; Erik Dean ; et
al. |
August 5, 2021 |
Atraumatic Occlusive System with Compartment for Measurement of
Vascular Pressure Change
Abstract
A method of delivering a therapeutic agent into a patient vessel
with a delivery device is provided. The delivery device includes an
infusion lumen through which the agent is delivered, a vessel
occluder that can be operated between a collapsed and an expanded
configuration, and when in the expanded configuration occludes the
vessel, and a pressure sensor shielded from the effects of
turbulent flow at an exit of the infusion lumen. The shield
pressure sensor is able to accurately sense pressure in the vessel.
The sensed pressure is used to determine a dwell time for the
vessel occluder in the expanded configuration.
Inventors: |
Olson; Erik Dean; (Castle
Rock, CO) ; Jaroch; David Benjamin; (Arvada, CO)
; McCain; Patrick Charles; (Denver, CO) ;
Arepally; Aravind; (Atlanta, GA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Surefire Medical, Inc. |
Westminster |
CO |
US |
|
|
Assignee: |
Surefire Medical, Inc.
Westminster
CO
|
Family ID: |
1000005534752 |
Appl. No.: |
17/236446 |
Filed: |
April 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16431547 |
Jun 4, 2019 |
|
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17236446 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/0215 20130101;
A61M 2025/0002 20130101; A61B 5/6853 20130101; A61B 17/12109
20130101; A61B 5/02007 20130101; A61M 25/10181 20131105; A61M
2025/09008 20130101; A61B 17/12136 20130101; A61B 2017/1205
20130101; A61B 17/1204 20130101; A61M 25/09 20130101 |
International
Class: |
A61B 17/12 20060101
A61B017/12; A61B 5/0215 20060101 A61B005/0215; A61M 25/09 20060101
A61M025/09; A61M 25/10 20060101 A61M025/10 |
Claims
1. A method of delivering a therapeutic agent to a patient,
comprising: a) providing a system for temporarily occluding a blood
vessel, including, i) a flexible tubular member having a proximal
end and a distal end, an infusion lumen extending between the
proximal and distal ends, the infusion lumen having a distal
orifice at the distal end, wherein when a therapeutic agent is
infused through the orifice, eddy currents are generated about the
orifice, and ii) an expandable occluder mounted at the distal end
of the tubular member, the occluder defining a chamber, the distal
end of the tubular member extending through the occluder such that
the orifice opens distal of the occluder, iii) a first pressure
sensor to sense fluid pressure in the blood vessel distal of the
occluder, the first pressure sensor isolated from pressure changes
induced by the eddy currents; b) advancing a distal end of the
system to a target vein of an organ; c) expanding the occluder
within the target vein; d) communicating fluid between the chamber
of the occluder and the target vein distal of the occluder; e)
sensing a baseline pressure in the target vein distal of the
occluder; f) delivering a therapeutic agent through the infusion
lumen and out of the orifice; and g) using the first pressure
sensor to monitor pressure in the target vein distal of the
occluder during the delivery.
2. The method of claim 1, further comprising: using a pressure
gradient between the monitored pressure and baseline pressure to
determine progress of the delivery.
3. The method of claim 1, further comprising: using a pressure
gradient between the monitored pressure and baseline pressure to
determine a dwell time in which to keep the occluder expanded
within the target vein.
4. The method of claim 3, further comprising: leaving the occluder
expanded within the vein for at least the determined dwell
time.
5. The method of claim 1, wherein the baseline pressure is measure
with the first pressure sensor prior to expanding the occluder
within the vein.
6. The method of claim 1, wherein the baseline pressure is
monitored with a second pressure sensor located to sense fluid
pressure in the blood vessel proximal of the occluder.
7. A method of measuring pressure in a vessel distal of an
artificial temporary vessel occluder delivered into the vessel,
comprising: a) providing a system for temporarily occluding a blood
vessel, including, i) a flexible tubular member having a proximal
end and a distal end, an infusion lumen extending between the
proximal and distal ends, the infusion lumen having a distal
orifice at the distal end, wherein when a therapeutic agent is
infused through the orifice, eddy currents are generated about the
orifice, and ii) an expandable occluder mounted at the distal end
of the tubular member, the distal end of the tubular member
extending through the occluder such that the orifice opens distal
of the occluder, iii) a first pressure sensor to sense fluid
pressure in the blood vessel distal of the occluder, the first
pressure sensor isolated from pressure changes induced by the eddy
currents, and iv) a second pressure sensor to sense fluid pressure
in the blood vessel proximal of the occluder, the second pressure
sensor isolated from the blood distal of the occluder by the
occluder when the occluder is expanded across the blood vessel; b)
advancing a distal end of the system into a vessel; c)
communicating fluid between the chamber of the occluder and the
vessel distal of the occluder; d) sensing a baseline pressure in
the vessel distal of the occluder with the first sensor; e) sensing
a baseline pressure in the vessel proximal of the occluder with the
second sensor; and f) performing a function on the data received
from the first and second sensors to remove variations in the data
from the first sensor due to physiological phenomena.
8. A method according to claim 7, further comprising: infusing a
therapeutic agent through the infusion lumen and out of the distal
orifice; and performing a function on the data received from at
least the first sensor to remove variations in the data due to
turbulent flow from the therapeutic agent exiting the distal
orifice.
9. A method of delivering a therapeutic agent into a target tissue
through a vessel, comprising: a) providing a system for temporarily
occluding a blood vessel, including, i) a flexible tubular member
having a proximal end and a distal end, an infusion lumen extending
between the proximal and distal ends, the infusion lumen having a
distal orifice at the distal end, and ii) an expandable occluder
mounted at the distal end of the tubular member, the distal end of
the tubular member extending through the occluder such that the
orifice opens distal of the occluder; b) advancing a distal end of
the system into a vessel; c) expanding the occluder to block blood
flow past the occluder within the vessel; d) then infusing a
therapeutic agent through the infusion lumen and out of the distal
orifice into the vessel distal of the occluder; and e) leaving the
occluder expanded for at least a dwell time sufficient for
transport of the therapeutic agent through the vessel wall and into
the target tissue.
10. The method according to claim 9, wherein infusion of the
therapeutic agent generates a pressure gradient in the vessel on
the proximal and distal sides of the occluder, and the pressure
gradient, at least in part, affects the transport of the
therapeutic agent.
11. The method according to claim 9, wherein the system includes a
first pressure sensor to measure a first fluid pressure of blood in
the vessel distal of the occluder, and a second pressure sensor to
measure a second fluid pressure of blood in the vessel proximal of
the occluder, and the measured pressure gradient is a differential
between the first and second fluid pressures.
12. The method according to claim 9, wherein the dwell time is
calculated based, at least in part, on the diffusion rate of a
molecule of the therapeutic agent.
13. The method according to claim 12, wherein the diffusion rate of
the molecule is predicted, at least in part, by the molecular mass
of the molecule.
14. The method according to claim 9, wherein one of the at least
one therapeutic agent at least partially replaces the oxygen and/or
nutrient requirements of the target tissue.
15. The method according to claim 9, wherein the transport rate of
the therapeutic agent is calculated, at least in part, by osmotic
characteristics of the therapeutic agent in the vessel.
16. The method according to claim 9, further comprising: sensing a
fluid pressure in the vessel distal of the occluder, wherein when
the therapeutic agent is infused out of the orifice, eddy currents
are generated about the orifice, and the system includes a pressure
sensor to measure a fluid pressure in the vessel distal of the
occluder, and the pressure sensor is shielded from the eddy
currents.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. Ser. No.
16/431,547, filed Jun. 4, 2019, which is hereby incorporated herein
by reference in its entirety.
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0002] The present invention relates to catheter-based occlusive
systems and intravascular methods to deliver a therapeutic agent
for the treatment of disease.
2. State of the Art
[0003] Veins are designed to carry blood from the tissue back to
the heart. This results in several physiological differences
relative to the arteries. Key among these features is that they are
configured to carry a relatively large volume of low-pressure
blood. They therefore tend to have larger lumens and less muscle
and elastic tissue relative to comparable arteries. Temporary
occlusion of the vein therefore requires a device with large
diameter sufficient to fill the venous channel without exerting
high radial forces on the weaker vessel walls.
[0004] The most common occlusion device is the vascular balloon.
These devices function by inflating a flexible or semi flexible
membrane using fluid pressure through a lumen in communication with
an operator. The inflation of the balloon to an appropriate size is
typically monitored by fluoroscopy by injection of precise
quantities of contrast fluid to inflate the balloon, followed by
infusion of a bolus of contrast through the infusion lumen of the
device to determine if blood flow persists. Balloon volume must be
closely monitored as even small degrees of over inflation result in
high radial force applied to the vessel wall.
[0005] In the arterial network, the use of balloons is common
place. The structure of the arterial vessels, having a thick layer
of muscle and elastic fiber matrix, allows for a high degree of
variability in inflation of the device without rupture.
[0006] In distinction, the venous system presents a number of
challenges when using balloons. The larger veins require larger
balloon diameters, making precise control of inflation challenging.
Furthermore, the weaker and less elastic structure of the vein is
less resistant to the high radial force exerted by the balloon.
This in turn results in complications such as vessel rupture and
dissection.
[0007] Co-owned U.S. Pat. Nos. 9,770,319 and 9,968,740 to Chomas
teach several therapeutic catheter-based dynamic microvalve
occlusion systems that automatically open and close based on
relative fluid pressure conditions about proximal and distal sides
of the microvalve. These occlusive systems provide excellent
occlusion while exerting low radial force on the vessel wall.
However, the systems described in Chomas are not adapted to provide
the user accurate information on the pressurization to which the
treated vessels are subject or whether the interstitial fluid
pressure in the treated tissue is overcome. In particular, the
interstitial fluid surrounds and exerts pressure upon the vessels.
The interstitial fluid pressure in a tumor is a physiological
parameter with demonstrated predictive value for a tumor's
aggressiveness, drug delivery, as well as response to treatments
such as radiotherapy and chemotherapy. The interstitial fluid
pressure is generally high relative to the blood pressure within
the vein, indicating a strong inclination of molecules to flow from
the interstitial fluid into the veins. Thus, the interstitial fluid
pressure biases the vein against therapeutic uptake.
SUMMARY
[0008] An atraumatic vessel occlusive system includes a flexible
tubular member having a proximal end, a distal end, and defining an
infusing lumen extending between its proximal and distal ends, a
diametrically adjustable vessel occluder mounted at the distal end,
and at least one pressure sensor.
[0009] In an embodiment, the flexible tubular member includes an
inner catheter longitudinally displaceable relative to an outer
catheter. The inner catheter defines the infusion lumen with a
distal orifice and a flush lumen is defined at least in part by the
outer catheter and preferably between the inner and outer
catheters.
[0010] In an embodiment, the occluder is coupled to the distal ends
of each of the outer and inner catheters such that when the inner
catheter is longitudinally displaced in a distal direction relative
to the outer catheter, the occluder diametrically collapses into an
elongate ovoid delivery configuration sized for passage through a
vessel, and when the inner catheter is longitudinally displaced in
a proximal direction relative to the outer catheter, the occluder
diametrically expands into an occlusive configuration adapted to
extend across the wall of the vessel. The expanded occlusive
configuration defines a chamber within the occluder. The occluder
has a fluid impermeable proximal portion and a fluid permeable
distal portion that allows fluid communication between the vessel
distal of the occluder and the chamber.
[0011] In accord with one aspect of the system, the structure of
the occluder is formed as a microvalve of flexible braided
filaments with low radial force that will not over-pressurize the
wall of a vessel in which it is deployed. A fluid impermeable
membrane is provided over the proximal portion of the braided
construct. The distal portion of the braided construct is covered
in a fluid permeable coating or covering.
[0012] In accord with an embodiment of the system, a first pressure
senor is positioned within the chamber of the occluder. As a result
of the fluid communication between the chamber and the vessel, the
first pressure sensor is adapted to sense pressure in the vessel in
real time. Further, because the first pressure sensor is shielded
from the vessel by the fluid permeable membrane, the first pressure
sensor is not subject to the effects of turbulent flow occurring at
the distal orifice of the infusing lumen, as described further
below.
[0013] During therapeutic agent delivery, pressure readings can be
used to confirm placement of device and confirm absence of
collateral flow in vessels distal to the tip of the device.
Collateral flow is a condition in which circulation of blood is
established through the enlargement of minor vessels and re-routing
of vessels with those of adjacent parts when a vein or artery is
functionally impaired. It can be important that no collateral flow
exists to ensures that a fluidic therapeutic agent infused through
infusion lumen of device will reach target tissue in the organ, and
not be re-routed to non-target tissue. The change in pressure
gradient running from the arterial to venous side is caused by the
difference in volume within the vessels in the direction of flow.
The arterial side has less volume than does the venous side,
resulting in a pressure drop as blood flows from arteries to veins.
The characteristic increase in pressure when a vein is occluded is
an indicator that there is not collateralization of the tissue
compartment, as collateral flow will offer an alternative path for
blood flow and will prevent a pressure increase.
[0014] In accord with another aspect of the system, a second
pressure sensor is positioned proximal to the diameter of the
occluder. A gradient between the first and second pressure sensors
can directly determine when pressure in the vessel increases
relative to systemic pressure. The presence of both sensors allows
for real time calculation of such gradient.
[0015] In accord with another aspect of the system, an actuation
handle is provided at proximal ends of the inner and outer
catheters to effect relative displacement thereof. In addition, a
first port is provided at the handle in fluid communication with
the inner catheter for delivering a first fluid into the infusion
lumen and out into the vessel. A second port is also provided at
the handle in fluid communication with the outer catheter for
delivering a second fluid through the flush lumen, into the
chamber, and out of the fluid permeable distal portion of the
occluder.
[0016] In accord with a method, the system is advanced to a target
vessel of an organ in accord with known procedures. In a preferred
method, the device is tracked through the venous system in the
delivery configuration. The first and/or second pressure sensors
are utilized to obtain a systemic reference pressure. The handle is
actuated to retract the inner catheter relative to the outer
catheter and thereby deploy the occluder into the occlusive
configuration within the vein, in which it has a squatter, ovoid
shape with an expanded diameter. The occluder occludes venous flow
as the pressure of the blood flow within the vein applies force
against the distal side of the occluder.
[0017] Blood fills the chamber of the occluder through the fluid
permeable coating or covering. Alternatively, a fluid is infused
through the flush lumen to fill the chamber and flow out into the
vessel, thus placing the chamber and vessel in fluid continuity.
The first pressure sensor within the chamber of the occluder is
then able to provide a constant pressure monitoring of the vessel
on the distal side of the occluder.
[0018] A therapeutic agent is then infused through the infusion
lumen and out of the distal orifice, beyond the occluder. Infusion
of therapy proceeds while pressure is monitored, allowing a user to
determine if over pressurization is experienced and if interstitial
fluid pressure within the tissue of the organ is overcome. The
infusion of therapy can create local eddy currents in the fluid
near the tip of the device. While this could otherwise prevent
accurate readings of pressure during infusion if the sensor is
placed at the device tip, the sensor by being placed within the
chamber is protected from such currents. The apertures in or
permeability of the distal portion of the occluder allows for fluid
communication between the chamber and the distal vascular
compartment. During infusion, pressure in the distal vasculature
and the chamber equalize due to the apertures in the distal
membrane. However, these apertures are sufficiently small to dampen
turbulence generated by the distal tip, allowing for stable
pressure readings by the first sensor. The stable pressure readings
permit accurately identifying the pressure at the arterial side of
the occluder.
[0019] The second sensor, located proximal to the expanded occluder
can be used to monitor systemic pressure during infusion. Using the
data from the first and second sensors, it can be more directly
determined when pressure distal of the occluder increases relative
to systemic pressure. The presence of both sensors allows for real
time calculation of pressure differentials, while a single tip
based sensor requires determining a systemic reference point prior
to device deployment and subsequent infusions.
[0020] Then, during infusion of a therapeutic agent, the pressure
gradient between the arterial side of the vein (from the first
pressure sensor) and the return venous side (from the second
pressure sensor) is monitored. If the gradient identifies a higher
pressure on the distal side, such indicates that there is not yet
collateralization of the tissue compartments, as collateral flow
will offer an alternative path for blood flow and will prevent such
pressure gradient. Infusion of therapy proceeds while pressure is
monitored, allowing the user to determine if over-pressurization is
experienced and if interstitial fluid pressure within the tissue is
overcome.
[0021] In addition, according to one aspect of the method, the
therapeutic agent can be infused at a flow rate that will generate
a vascular pressure gradient which increases therapeutic diffusion
rate through the venous and capillary vasculature. A dwell function
can be applied to optimize diffusion of the therapeutic agent into
the tissue given a measured pressure gradient. The dwell time of
the dwell function will depend on the therapeutic agent and the
measured pressure gradient. The larger the measured pressure
gradient, a shorter dwell time is required for optimal diffusion of
the therapeutic agent into the tissue.
[0022] The occluder can remain expanded within the vessel for the
duration of the dwell time until the therapy has been infused and
therapeutic uptake to occur without being washed away in venous
blood flow. The proximal handle is then actuated to collapse the
occluder, and the system is then removed from the anatomy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a perspective view of an atraumatic occlusive
system as described in an embodiment herein.
[0024] FIG. 2 is an enlarged schematic side elevation view of the
distal side of the system of FIG. 1, shown with an occluder in a
reduced diameter configuration for guidance to a target vessel.
[0025] FIG. 3 is a view similar to FIG. 2, shown with the occluder
in an enlarged diameter configuration for occlusion of the target
vessel.
[0026] FIG. 4 is a flow chart of a method of using the system.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] With reference to the following description, the terms
"proximal" and "distal" are defined in reference to a user of the
device, with the term "proximal" being closer to the user's hand,
and the term "distal" being further from the user such as to be
located further within a body of the patient during use.
[0028] Apparatus and methods are described herein related to the
use of a system to inject a therapeutic agent into a primary vessel
communicating with a diseased tissue of an organ, for example, a
tumor. For example, the tumor to be treated can be a solid tumor.
In some cases, the tumor can be a cancerous tumor, such as a tumor
specific to, by way of example only, cancer of the pancreas,
kidney, liver, lung, or uterus.
[0029] As described herein, a treatment system is used to provide a
therapeutic agent into a solid tumor by targeted infusion of the
treatment into a region of tissue. The therapeutic agent is
injected under relatively high pressure into a region of an organ
or other defined area of tissue served by one or more feeder
vessels.
[0030] Turning now to FIGS. 1 and 2, an atraumatic vessel occlusive
system 10 is shown. The system 10 includes a flexible tubular
member 12 having a proximal end 14 a distal end 16. The tubular
member 12 defines an infusing lumen 18 extending between its
proximal and distal ends. A diametrically adjustable vessel
occluder 20 is mounted at the distal end 16 of the tubular member.
The system also includes at least one pressure sensor 22, 24,
located and functioning as described below.
[0031] In an embodiment, the flexible tubular member 12 includes an
inner catheter 30 telescopically advanceable within an outer
catheter 32. The inner catheter 30 has a proximal end 34 and distal
end 36, and the outer catheter 32 also has a proximal end 38 and
distal end 40. The infusion lumen 18 is preferably defined through
the inner catheter 30 and opens to a distal axial orifice 84, and a
separate flush lumen 42 is preferably defined in the toroidal space
between the inner and outer catheters. Alternatively, the flush
lumen may extend through the wall of either of the inner and outer
catheters 30, 32.
[0032] In accord with a preferred aspect of the system, an
actuation handle 50 is provided at the proximal ends 34, 38 of the
inner and outer catheters 30, 32 to effect relative displacement of
the thereof. The actuation handle 50 includes a stationary member
52 and a movable member 54, such as a slide longitudinally
displaceable relative to the stationary member. The stationary
member 52 is provided with a side port 56, and a strain relief 58
connects the proximal end 38 of the outer catheter 32 to the
stationary member 52. The side port 56 is in fluid communication
with the outer catheter 32. The movable slide 54 is coupled to the
inner catheter 30. A hypotube 60 is coaxially inserted around the
proximal end of the inner catheter 34 to provide mechanical support
of the inner catheter. The proximal end of the slide 54 defines an
infusion port 62 that is fluidly coupled to the proximal end 34 of
the inner catheter 30. The actuation handle 50 also includes a
releasable lock 64 that, when actuated, can retain the movable
member 54 and stationary member 62 in relatively fixed longitudinal
positions. The handle 50 may also include a display 66 and
associated memory and logic to permit the display of real-time
and/or stored pressure data read from the first and second sensors
22, 24, as well as calculated relationships between the pressures
read from sensors 22, 24, such as a gradient between the two.
Button 68 near display permits actuation of the logic and display
as well as cycling through various logic functions.
[0033] The occluder 20 is a microvalve comprising a braided
construct of filaments 70. The proximal end of the filaments 70 are
coupled to, and preferably rigidly fixed to, the distal end 40 of
the outer catheter 32, and the distal end of the filaments 70 are
coupled to, and preferably rigidly fixed to, the distal end 36 of
the inner catheter 30. The general construct of the braided valve
portion of such a microvalve device is described in detail in
co-owned U.S. Pat. Nos. 8,696,698 and 9,770,319, both of which are
hereby incorporated by reference herein in their entireties.
Longitudinal displacement of the inner catheter 30 relative to the
outer catheter 32 results in the microvalve moving between a first
elongate ovoid configuration of smaller diameter (FIG. 2) adapted
for guiding to a deployment location in a vessel, and a second
squatter ovoid configuration of a larger diameter adapted for
occlusion of the vessel (as shown in FIG. 3). That is, in both the
first and second configurations, the microvalve is of an ovoid
configuration and has a generally symmetrically shape about a
longitudinal central axis A and a plane P orthogonal to the central
axis A of the microvalve at its area of maximum diameter. It is
recognized that the occluder can be moved through the first and
second configurations, and any size of configuration therebetween
to best suit the vessel in which it is used. The lock 64 on the
handle 50 can facilitate retaining the occluder 20 in a desired
size configuration during therapeutic treatment. The system 10 can
be advanced in the first elongate configuration to a deployment
location in a blood vessel over a guidewire (not shown) inserted
through the infusion lumen 18 of the inner catheter 30. The
interior of the occluder 20 defines a chamber 82.
[0034] In accord with one aspect of the occluder 20, a fluid
impermeable membrane 72 is provided over the proximal portion 74 of
the braided construct. Suitable materials for the impermeable
membrane include elastomeric natural and artificial rubbers,
silicones, styrenics, olefinics, copolyesters, polyurethanes and
polyamides. In accord with another aspect of the occluder, a fluid
permeable coating or covering 76 is provided over a distal portion
78 of the braided construct. Suitable materials for the fluid
permeable coating 76 include elastomeric natural and artificial
rubbers, silicones, styrenics, olefinics, copolyesters,
polyurethanes and polyamides processed so as to have micro or macro
scale perforations, channels, pores, or fibrous rather than
continuous morphology. This may be accomplished by physical
perforation techniques, by electrospinning or melt spinning fibers,
by inclusion of soluble components that can be removed during
processing to leave pores or voids, and by the addition of open
pore foaming agents or other suitable technology. The coating or
covering 76 can include a material placed over the outer surface of
the filaments 70, within the inner surface of the filaments, or a
combination thereof. The coating or covering 76 can extend only
between the filaments. The coating or covering 76 can be
free-floating on the filaments or can be rigidly fixed to the
filaments. The coating or covering 76 can be applied by dip
coating, spraying, sewing, bonded application, or other suitable
technology. The fluid permeable material 76 can be an otherwise
impermeable material made permeable by perforations or apertures
80. The fluid permeable material may be formed with interstices or
openings 80 providing a permeability that meets the requirements of
fluid permeability, as described below. The apertures,
perforations, interstices, openings, etc. (collectively referred to
hereinafter as `apertures` 80) within the fluid permeable material
may be geometrically arranged. The total cross-sectional surface
area of the apertures should be sufficiently large so as to
facilitate measurement of physiological response and infusion
pressure while dampening short duration turbulent flow. Most
preferably, apertures should be arranged in a radially symmetric
fashion so as to maintain uniform radial bending properties of the
device.
[0035] As the flush lumen between the inner catheter and outer
catheter is in fluid communication with the proximal infusion port,
a pressure sensor may reside within this space and still monitor
pressure experienced at the distal tip as long as the proximal
infusion port is sealed (creating a closed pressure chamber in
communication with the distal tip of the catheter). Sensor
responsiveness within this chamber is governed by the
cross-sectional surface area of the flush lumen and by the length
between the sensor and the distalmost aperture. The delay in
pressure response time decreases with increasing cross-sectional
area and decreasing length. For example, a device having a flush
lumen with a cross-sectional area of 0.5 mm.sup.2 and a sensor
located 100 cm from the distal aperture will require 2-5 seconds to
respond and stabilize to a change in pressure; whereas, a device
having a flush lumen with a cross-sectional area of 0.5 mm.sup.2
and a sensor located 50 cm from the distal aperture will require
1-3 seconds to respond and stabilize to a change in pressure; and
whereas, a device having a flush lumen with a cross-sectional area
of 2 mm.sup.2 and a sensor located 100 cm from the distal aperture
will require 0.1-0.5 seconds to respond and stabilize to a change
in pressure. The proximity of the sensor is therefore governed by
the duration of the physiological response intending to be
monitored. For instance, the infusion of therapeutics may be
administered over a range of time. For infusions occurring in
seconds and having transient pressure changes, the sensor should be
placed within a space of sufficient cross-sectional surface area
and at a sufficiently short distance from the distal aperture so as
to monitor pressure changes occurring within a second (or less).
Moreover, the pores at the distal end of the filter should be
sufficiently small and have a relatively low cross-sectional area
so that pressure fluctuations on the order of 0.01-0.2 seconds are
dampened while the sensor responds in the 0.2-1 second time
frame.
[0036] In one embodiment, a first pressure sensor 22 is mounted
within the chamber 82. The first pressure sensor 22 may be mounted
on the outer wall of the portion of the inner catheter 30 that
extends within the occluder (as shown), on an inner portion of the
filamentary braid, or another structure located within the chamber.
The material covering or coating 76 on the distal portion 78 of the
occluder 20 must be sufficiently fluid permeable such that when the
occluder is positioned in a fluid-filled vessel and the chamber 82
is filled with a fluid, both the chamber and the distal vessel
compartment will be subject to the same pressure conditions. Thus,
the first pressure sensor 22 can accurately sense the fluid
pressure conditions external of the occluder in the distal vascular
compartment of the target vessel. However, the fluid permeable
material 76 should effect a sufficient barrier to dampen turbulence
generated at the orifice 84 of the infusion lumen during
therapeutic infusion and the pressure effects thereof from causing
pressure instability at the interior chamber of the occluder and a
consequent deleterious effect on obtaining accurate pressure
readings of the distal vascular compartment of the target
vessel.
[0037] In accord with another preferred aspect of the system, a
second pressure sensor 24 is preferably positioned proximal to the
occluder 20. The second pressure sensor 24 is adapted to sense and
monitor systemic pressure. The second pressure sensor 24 is also
used in conjunction with the first pressure sensor 22 to determine
pressure differentials; i.e., to determine when the distal vascular
compartment pressure is higher than systemic pressure and by how
much.
[0038] The use of both the first and the second sensors 22, 24
allows for a real time calculation of the pressure gradient across
the occluder 20. As an alternative, the first pressure 22 alone can
be used to determine a pressure gradient by obtaining a reference
or baseline pressure reading prior to opening the occluder 20
across the vessel wall. Subsequent pressure readings from the first
pressure sensor 22 are then compared to the baseline pressure to
determine a gradient. The use of the gradient is described
below.
[0039] Turning now to FIG. 4, in accord with a method of using the
system, the distal end of the system is advanced at 100 in the
first elongate configuration to a target vessel of an organ in
accord with known procedures. In that manner, the system 10 can be
tracked over a guidewire through the venous system to the intended
location. The target vessel is preferably a vein receiving a return
supply of blood from an organ. By way of example, the organ can be
the liver and the target vessel can be the saphenous vein, or the
organ can be pancreas and the target vessel can be portal vein.
Other organs can be similarly treated through associated target
vessels, preferably wherein the target vessel is a vein.
[0040] The handle 50 is then actuated to move the inner catheter 30
relative to the outer catheter 32 and expand the diameter of the
occluder 20 at 102 to bring the outer surface of the occluder into
apposition with the vessel wall. The handle lock 64 can be operated
to fix the occlusive configuration (size and shape) of the occluder
20 within the vessel. The occluder 20 occludes venous flow as the
arterial side pressure of the blood flow within the vein applies
force against the distal side of the occluder which urges the
occluder into an open, expanded configuration.
[0041] Blood may begin to fill the chamber 82 of the occluder 20
through the apertures 80 of the fluid permeable coating or
covering. Additionally or alternatively, a fluid such as saline or
a similar flushing fluid can be infused from the second port 56,
through the flushing lumen 42, and into the chamber 82 of the
occluder. Because of the apertures 80 in the distal portion 78 of
the occluder, the occluder does not necessarily inflate under
pressure of the flushing fluid; rather the flushing fluid is
intended to place the first sensor 22 in continuous fluid contact
with the blood located external of the occluder. Once there is
fluid continuity at 104, the pressure outside the occluder 20 and
through the apertures can be sensed in real-time at the first
sensor at 106. A baseline pressure reading of the vessel is
preferably obtained.
[0042] Then, the therapeutic agent is infused at 108 through the
infusion lumen 18 and out of the distal orifice 84 of the inner
catheter, beyond the occluder 20. Infusion of therapy proceeds
while pressure in the vessel distal of the occluder and optionally
proximally of the occluder is monitored. The infusion of therapy
out of the orifice of the infusion lumen can create local eddy
currents in the fluid near the distal tip of the system. In prior
systems, these eddy currents could prevent accurate pressure
monitoring of the vessel conditions during infusion. In distinction
therefrom, the first pressure sensor 22, within the chamber and
shielded by the fluid permeable material, is protected from the
deleterious effects of the eddy currents that obscure accurate
monitoring. The apertures in or permeability of the distal portion
of the occluder allows for fluid communication between the chamber
and the distal vascular compartment. During infusion, pressure in
the distal vasculature and the chamber equalize due to the
apertures in the distal membrane. However, these apertures are
sufficiently small and geometrically arranged as to dampen
turbulence generated by the distal tip, allowing for stable
pressure readings by the embedded first sensor. The stable
(non-turbulent) pressure readings permit accurately identifying the
pressure at the arterial side of the occluder. In addition, the
second sensor 24, located proximal to where the expanded occluder
20 meets the vessel wall can be used to monitor at 110 the systemic
pressure in real-time during infusion. This accurate pressure data
can be used to determine pressure conditions within the tissue of
the organ; i.e., whether over pressurization conditions exist
and/or whether the interstitial fluid pressure within the tissue of
the organ is overcome.
[0043] The second sensor 24 will be completely shielded from
turbulent flow by the impermeable portion of the occluder 20. It
therefore monitors physiological pressure variations from
heartbeat, breathing, and other physiological phenomena. These
variations from physiological phenomena occur on the 100 s of
milliseconds to seconds timeframe. The distal first sensor 22 also
measures changes from physiological phenomena, as well as infusion
of therapy and turbulence. Turbulence occurs over a very short time
frame and can be filtered based on reference to the smoother
pressure profile of the second sensor 24. While the porous nature
of the distal occluder 20 geometry physically `prefilters` the
majority of noise from turbulent flow that would otherwise occur
around the first sensor 22, in one embodiment of the method, it is
contemplated that the noise from physiological phenomena is also
reduced. Variations in measured pressure due to heartbeat,
breathing, and other physiological phenomena registered on the
proximal second sensor 24 can be subtracted from the distal first
sensor 22 measurement, leaving only the pressure changes associated
with infusion. In accord with the method, data processing of the
received pressure data from the first and second sensors 22, 24
uses a filtering function to subtract turbulent flow data (short
time frame pressure variation) and a subtraction function to remove
variation due to broader physiological change. The filtering
algorithm produces a pressure reading resulting from only the
infusion of therapeutic agent through the infusion lumen.
[0044] Further, the real-time data from the first and second
sensors allows a more direct determination of when pressure distal
of the occluder increases relative to systemic pressure; i.e., when
the first sensor senses higher pressure than the second sensor, as
determined at 110.
[0045] During infusion of the therapeutic agent, the calculated
gradient between the arterial feed of the vein (from the first
pressure sensor) and the return venous side (from the second
pressure sensor) permits monitoring progress of the therapeutic
treatment at 112.
[0046] If the gradient identifies a higher pressure on the distal
side, such indicates that there is not yet collateralization of the
tissue compartments, as collateral flow will offer an alternative
path for blood flow and will prevent such pressure gradient.
Infusion of therapy proceeds while pressure is monitored, allowing
the user to determine if over-pressurization is experienced and if
interstitial fluid pressure within the tissue is overcome.
[0047] According to another aspect of a method with the system, the
therapeutic agent can be infused through the device at a flow rate
that will generate a vascular pressure gradient which increases the
therapeutic diffusion rate through the venous and capillary
vasculature.
[0048] To appreciate this advantage it is necessary understand that
molecules residing within the blood or other fluid filter through
the vessel based on pressure differentials between the fluid within
the vessel and the surrounding tissues. In the arterial side,
pressure is typically higher within the vessel than the surrounding
interstitial pressure. This positive pressure gradient forces
molecules out of the arterial end of the capillary bed and into the
tissue. As blood travels through the arterial vessel, pressure
drops, reducing the positive pressure gradient until no gradient is
present and pressure mediated filtration of molecules through the
vessel halts. On the venous side of the capillary bed a negative
gradient is present, causing reabsorption of molecules back into
the venous side capillaries and into systemic circulation. The
change in pressure from the arterial side to the venous side is a
result of difference in volume within the vessels in the direction
of flow; the arterial side has less volume than the venous side
resulting in a pressure drop as blood flows from arteries to
veins.
[0049] When a vein becomes blocked by expansion of the occluder 20
across the vein, blood flow stops. Blood, being an incompressible
fluid composed primarily of water, then equilibrates to the
arterial side pressure.
[0050] The resulting change in pressure increases the volume of
vessels experiencing a positive pressure gradient to the
surrounding tissue, including venous vessels. This allows material
to diffuse from the blood vessel outward throughout the entire
tissue volume. The effect takes place in tissues that normally have
a negative pressure gradient in which fluid and molecules would
normally filter from the tissue into the vasculature. Thus,
treatment of tissue on both the arterial and venous side is
enabled. The duration and extent of the diffusion across the vessel
wall and into the tissue can be controlled by the duration during
which the occluder is left in the enlarged second configuration.
Pressure may be further modulated by injecting one or more
additional volumes of fluid into the venous network distal of the
occluder. For example, one or more bolus injections of saline can
be injected into the vessel to modify uptake of the therapeutic
agent.
[0051] More specifically, the system when in position is used to
sense pressure in the vessel volume distal of the occluder. This
permits confirmation that the pressure in this volume is increased
relative to a baseline pressure. Then, a therapeutic agent is
infused through the infusion lumen into the vessel volume. The
occluder is left open in the expanded configuration within the
vessel according to a dwell function that identifies parameters for
optimum diffusion across the vessel wall. For example, the dwell
function can depend on the therapeutic agent (e.g., size of the
molecule and molecular interaction with the vessel wall) and the
measured pressure gradient. Holding other parameters constant, the
larger the measured pressure gradient, the less time is required
for optimal diffusion of the therapeutic agent into the tissue. The
dwell time for a therapeutic maximizes the time in which the
therapeutic resides within the target vasculature or, in other
words, leaves the occluder open until the concentration of
therapeutic in the blood of the vessel approaches zero and the
concentration of the therapeutic in the surrounding target tissue
increases to maximum availability from the dose. As the occluder
blocks blood flow, this time is dependent upon the metabolic
requirements of the tissue. In most cases the occluder may remain
in place for up to 30 minutes before ischemic damage occurs to the
tissue. This duration may be increased by the use of infusates that
partially or totally replace the oxygen and nutrient requirements
of the target tissues. By way of exemplar, such infusates include
oxygenated saline or phosphate buffered solutions, Ringer's
solutions, cellular growth mediums such as RPMI, MEM (minimal
essential media), and DMEM, and intravenous sugar solutions such as
5% dextrose solution. Baring the metabolic needs of the surrounding
tissue, the diffusion rate of the therapeutic molecule as predicted
by molecular mass and positive pressure gradient measurements from
the pressure sensor can be used to calculate therapeutic diffusion
depth for a given dwell time. As capillaries typically rest no
further than 100 .mu.m from a given volume of tissue, the dwell
time can be calculated to ensure full penetration of therapeutic to
this depth.
[0052] A typical diffusion rate for a small molecule such as
doxorubicin is on the order of 0.2-1 .mu.m/sec at physiological
pressure differentials of 10-30 mmHg from the vessel to surrounding
tissue, allowing the drug to diffuse through the 100 .mu.m tissue
volume in 2-8 minutes. Higher molecular weight biological
protein-based agent such as Immunoglobulin G (IgG) have much lower
diffusion rates on the order of 0.0002 .mu.m/sec at physiological
pressure differentials of 10-30 mmHg, resulting in a diffusion time
of 60 minutes to fully penetrate a 100 .mu.m tissue volume. As the
pressure differential increases, the rate of diffusion
increases.
[0053] Various models can be used to calculate the diffusion rate
of a molecule through the tissue. Most such models are based around
Fick's law of diffusion in which diffusion occurs in response to a
concentration gradient expressed as the change in concentration due
to a change in position. The local rule for molecular movement or
flux J is given by Fick's 1st law of diffusion:
J = - - .chi. .times. .differential. C .differential. x ,
##EQU00001##
[0054] in which the flux J [cm.sup.-2 s.sup.-1] is proportional to
the diffusivity .chi.[cm.sup.2/s] and the negative gradient of
concentration,
.differential. C .differential. x .function. [ cm - 3 .times. cm -
1 ] .times. .times. or .times. [ cm - 4 ] . ) ##EQU00002##
[0055] Then, the distance of molecular penetration can be estimated
by considering steady-state transport in one spatial dimension,
wherein c(x) is concentration as a function of distance x,
c(0)=c.sub.0 is the source concentration, and x is the distance
from the source, such that c.fwdarw.0 as x.fwdarw..infin.. Assuming
first order uptake kinetics, with an uptake rate of k.sub.uc, then
for diffusion-dominated transport,
c = c 0 ( - x d p ) , ##EQU00003##
where
d p = ( D k u ) 1 2 ##EQU00004##
[0056] where, D is the diffusivity and d.sub.p is the
characteristic penetration distance. It is calculated how long it
takes for the concentration (c.sub.0) to approach 0, i.e., such
that the therapeutic agent has diffused out of the vessel and into
the surrounding tissue. Thus, the diffusive transport can be used
to calculate a transport rate of the therapeutic agent and
determine, in whole or in part, the consequent dwell time at which
the occluder is to remain in an open expanded configuration
post-infusion for appropriate therapeutic uptake into the target
tissue.
[0057] It is also known that transport of molecules can be affected
by pressure gradients. For convection-dominated transport with
first-order kinetics based on the pressure differential between the
vessel and the interstitial tissue, the equation can be applied
with dp=u/ku, where u is the fluid velocity. As before, it is
calculated how long it takes for the concentration (c.sub.0) to
approach 0, i.e., such that the therapeutic agent has diffused out
of the vessel and into the surrounding tissue. Thus, the measured
pressure gradient from the first and second sensors 122, 124 can be
used to calculate a transport rate of the therapeutic agent and
determine, in whole or in part, the consequent dwell time at which
the occluder is to remain in an open expanded configuration
post-infusion for appropriate therapeutic uptake into the target
tissue.
[0058] Other factors such as the osmotic pressure can also be
considered, measured, evaluated, modified, and used to determine a
transport rate of the therapeutic agent and calculate, in whole or
in part, the consequent dwell time at which the occluder is to
remain in an open expanded configuration post-infusion for
appropriate therapeutic uptake into the target tissue.
[0059] In addition, it is contemplated that the factors such as
diffusion, pressure gradient, and/or osmotic pressure may be used
in combination of two more to calculate a dwell time at which the
occluder is to remain in an open expanded configuration
post-infusion for appropriate therapeutic uptake into the target
tissue.
[0060] Once the dwell time is complete and the dose of agent has
been delivered 114, no additional therapeutic agent is delivered at
116. The proximal handle 50 is then actuated at 118 to collapse the
occluder 20, and the system is then removed at 120 from the
patient.
[0061] In accord with another method, substantially similar to the
prior method, the system used includes a first (single) pressure
sensor (and no second pressure sensor). All operations can be
similarly performed with the exception that instead of constant
real-time systemic pressure monitoring from the second sensor by
which to compare the real-time, sensed distal vessel volume
pressure from the first sensor in determining a pressure gradient,
a baseline pressure is measured with the first pressure sensor
prior to expanding the occluder across the vessel wall and used as
a comparator for determining the gradient.
[0062] There have been described and illustrated herein embodiments
of systems and methods for intravascular delivery of a therapeutic
agent through a vessel to a tissue, such as an organ. While
particular embodiments of the invention have been described, it is
not intended that the invention be limited thereto, as it is
intended that the invention be as broad in scope as the art will
allow and that the specification be read likewise. Thus, it is
recognized that the systems and methods may be applied to both
humans and animals. Also, while examples of organs and disease
states have been provided, such lists are not meant to be exclusive
and the systems and methods are intended to be used where ever they
would have therapeutic utility, in association with any such
organs, disease states, and with any appropriate therapeutic agents
now known or hereinafter discovered or developed. Also, the
flexible tubular member can be any catheter arrangement meeting the
needs of the device claimed, i.e., permitting passage of the
therapeutic agent and actuation of the occluder. Further, while a
preferred occluder has been described, other occluders may be used
as well to assemble the systems and accomplish the methods
described herein. It will therefore be appreciated by those skilled
in the art that yet other modifications could be made to the
provided invention without deviating from its scope as claimed.
* * * * *