U.S. patent application number 13/647165 was filed with the patent office on 2013-05-23 for methods and devices for removal of a medical agent from a physiological efferent fluid collection site.
This patent application is currently assigned to Catharos Medical Systems, Inc.. The applicant listed for this patent is Catharos Medical Systems, Inc.. Invention is credited to Brian K. Courtney, Peter J. Fitzgerald, Ali H. Hassan, Lester John Lloyd, Binh Luong, Michael Orth, Mark Yang.
Application Number | 20130131614 13/647165 |
Document ID | / |
Family ID | 40156608 |
Filed Date | 2013-05-23 |
United States Patent
Application |
20130131614 |
Kind Code |
A1 |
Hassan; Ali H. ; et
al. |
May 23, 2013 |
Methods and Devices for Removal of a Medical Agent from a
Physiological Efferent Fluid Collection Site
Abstract
Methods and devices for selectively removing an agent from a
physiological site, e.g., a physiological efferent fluid collection
site, are provided. Aspects of the invention include fluid removal
(e.g., aspiration) devices having a fluid removal element and a
flow modulator positioned at a distal end of the fluid removal
element. The flow modulator is configured to converge intersecting
fluid flow paths into the fluid removal element. Also provided are
systems and kits for performing the subject methods. The subject
invention finds use in a variety of different applications,
including the selective removal of both therapeutic and diagnostic
agents from a variety of different physiological sites.
Inventors: |
Hassan; Ali H.; (Mountain
View, CA) ; Lloyd; Lester John; (Orinda, CA) ;
Orth; Michael; (Los Gatos, CA) ; Yang; Mark;
(Los Gatos, CA) ; Luong; Binh; (Los Gatos, CA)
; Courtney; Brian K.; (Toronto, CA) ; Fitzgerald;
Peter J.; (Portola Valley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Catharos Medical Systems, Inc.; |
Campbell |
CA |
US |
|
|
Assignee: |
Catharos Medical Systems,
Inc.
Campbell
CA
|
Family ID: |
40156608 |
Appl. No.: |
13/647165 |
Filed: |
October 8, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12138291 |
Jun 12, 2008 |
8308673 |
|
|
13647165 |
|
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|
60934511 |
Jun 13, 2007 |
|
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Current U.S.
Class: |
604/319 |
Current CPC
Class: |
A61M 1/3615 20140204;
A61M 1/008 20130101 |
Class at
Publication: |
604/319 |
International
Class: |
A61M 1/00 20060101
A61M001/00 |
Claims
1-28. (canceled)
29. A system for selectively removing an agent from a physiological
efferent fluid collection site, said system comprising: (a) an
aspiration element; (b) a flow modulator positioned at a distal end
of said aspiration element and that is configured to converge
intersecting fluid flow paths into said aspiration element; (c) an
aspiration mechanism operatively connected to said aspiration
element; (d) an actuation controller element for controlling
actuation of said aspiration mechanism.
30. The system according to claim 29, wherein said flow modulator
comprises an expandable frame of two or more longitudinal
elements.
31. The system according to claim 30, wherein said flow modulator
further comprises an impermeable membrane positioned between said
two or more longitudinal elements.
32. The system according to claim 31, wherein said impermeable
membrane is configured to produce an asymmetric fluid barrier upon
expansion of said expandable frame.
33. The system according to claim 29, wherein said aspiration
element and flow modulator are configured so that fluid flows past
said aspiration element when said aspiration element is not
activated.
34. The system according to claim 33, wherein said flow modulator
comprises a flow outlet positioned downstream of said flow
modulator.
35. The system according to claim 34, wherein said flow outlet is
configured to allow bidirectional fluid flow.
36. The system according to claim 34, wherein said flow outlet is
configured to allow unidirectional fluid flow.
37. The system according to claim 29, wherein said system further
comprises a hemodynamic sensor.
38. The system according to claim 37, wherein said sensor is
coupled to said flow modulator.
39. The system according to claim 29, wherein said system further
comprises a detector for at least predicting the presence of said
agent in said physiological efferent fluid collection site.
40. The system according to claim 39, wherein said detector
comprises a detection element that is introduced into said efferent
fluid collection site through said aspiration element.
41. The system according to claim 40, wherein said system further
comprises a positioning mechanism for positioning said detection
element in said efferent fluid collection site.
42. The system according to claim 41, wherein said positioning
mechanism is operatively coupled to said flow modulator.
43. The system according to claim 41, wherein said positioning
mechanism is operatively coupled to said aspiration element.
44. The system according to claim 39, wherein said detector is a
fiber optic detector.
45. The system according to claim 29, wherein said aspiration
element is present in an elongated tubular structure.
46. The system according to claim 45, wherein said elongated
tubular structure is a catheter device.
47. An aspiration device for selectively removing an agent from a
physiological efferent fluid collection site, said device
comprising: (a) an aspiration element; and (b) a flow modulator
positioned at a distal end of said aspiration element and that is
configured to converge intersecting fluid flow paths into said
aspiration lumen.
48-56. (canceled)
57. A kit for selectively removing an agent from a physiological
efferent fluid collection site, said kit comprising: (a) an
aspiration device for selectively removing an agent from a
physiological efferent fluid collection site, said device
comprising: (i) an aspiration element; and (ii) a flow modulator
positioned at a distal end of said aspiration element and that is
configured to converge intersecting fluid flow paths into said
aspiration lumen; and ructions for practicing the method of claim
1.
58-60. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Pursuant to 35 U.S.C. .sctn.119 (e), this application claims
priority to the filing date of U.S. Provisional Patent Application
Ser. No. 60/934,511 filed Jun. 13, 2007; the disclosure of which
application is herein incorporated by reference.
INTRODUCTION
[0002] Administration of therapeutic or diagnostic agents to a
subject is typically accomplished by either localized or systemic
routes. With many types of agents, localized delivery methods are
desirable. For example, medical compounds of interest may have
desired diagnostic or therapeutic effects within the region into
which they are introduced, but also exhibit toxic or other
undesirable effects when they are allowed to circulate elsewhere.
In certain cases, it is desirable to introduce a higher volume of a
compound to the local region than can be tolerated by other body
tissues if that volume were to ultimately cause the systemic
concentration to exceed a safe threshold.
[0003] A common example of such a compound is radio-opaque dye.
Iodinated forms of such a dye are used routinely during
catheter-based interventional procedures such as coronary, renal,
neurological and peripheral arteriography.
[0004] The iodine component has a high absorption of x-rays and
therefore provides a contrast medium for the radiological
identification of vessels when introduced within an upstream
artery. However, the use of such dyes is known to have potential
toxic effects depending on the specific formulation, including
direct injury to renal tubule cells, endothelial injury,
bronchospasm, inflammatory reactions, pro-coagulation,
anti-coagulation, vasodilation and thyrotoxicosis.
[0005] Other materials that may be introduced locally for desired
effects but whose direct or other effects would be undesired
elsewhere include vasoactive agents, cytotoxic agents, genetic
vectors, apoptotic agents, anoxic agents (including saline),
photodynamic agents, emboli-promoting particles or coils,
antibodies, cytokines, immunologically targeted agents and
hormones.
[0006] An important anatomic concept with respect to the
vasculature and other conduits supplying and draining an organ is
the principle that a tissue or organ and regions of the organ have
a limited number of primary supply conduits and a limited number of
draining conduits. Material introduced into the upstream side of
the target tissue will typically be dispersed among the diverging
arterioles and capillaries, which then converge into a collection
of common venules and vein (s) downstream, e.g., in a physiological
efferent fluid collection site. For example, the myocardium of the
heart is fed by the right coronary, left anterior descending and
left circumflex arteries. Each of these arteries enters a capillary
network that eventually converges into the small and middle cardiac
vein, anterior interventricular vein and posterior vein of the left
ventricle. These veins are all tributaries of the coronary sinus,
which may be viewed as a cardiovascular efferent fluid collection
site. Material introduced into any of the aforementioned coronary
arteries that travels through the capillary network will enter the
coronary sinus providing an opportunity to collect it before it
returns to the systemic circulation. In another example, the brain
is fed by the carotid and vertebral arteries which enter a highly
anastomotic network. Blood flow through the brain substantially
drains to the systemic circulation via a network of sinuses that
converge onto the internal jugular veins. In yet another example,
each kidney is substantially supplied by a renal artery and drained
by a renal vein. In yet another example, a tumor or metastatic
lymph node may have a set of primary afferent (supply) conduits and
a set of primary efferent (drainage) conduits. In yet another
example, the lungs are supplied by a pulmonary artery and its
branches, and are drained by the pulmonary veins and their
tributaries into the left atrium.
SUMMARY
[0007] Methods and devices for selectively removing an agent from a
physiological site, e.g., a physiological efferent fluid collection
site, are provided. Aspects of the invention include fluid removal
(e.g., aspiration, devices having a fluid removal element and a
flow modulator positioned at a distal end of the fluid removal
element. The flow modulator is configured to converge intersecting
fluid flow paths into the fluid removal element. Also provided are
systems and kits for performing the subject methods. The subject
invention finds use in a variety of different applications,
including the selective removal of both therapeutic and diagnostic
agents from a variety of different physiological sites.
BRIEF DESCRIPTION OF THE FIGURES
[0008] FIG. 1A provides a view of flow lamina in a coronary sinus,
where the coronary sinus is an example of a physiological efferent
fluid collection site. FIGS. 1B and 1C provide illustrations of
physiological sites from which fluid may be removed according to
certain embodiments of the invention.
[0009] FIG. 2A provides a view of flow lamina in a coronary sinus
that is redirected by a flow modulator according to an embodiment
of the invention. FIGS. 2B to 2E provide different views of various
flow modulator configurations according to certain embodiments of
the invention.
[0010] FIG. 3 illustrates a device according to an embodiment of
the invention.
[0011] FIGS. 4A to 4D illustrate fluid flow interactions with the
device of FIG. 3 during various phases of use.
[0012] FIGS. 5A to 5C provide various views of fluid removal
elements according to various embodiments of the invention.
[0013] FIGS. 6A and 6B provide an illustration of another type of
flow modulator that may be employed in certain embodiments of the
invention.
[0014] FIGS. 7A and 7B provide various views of different sensor
configurations that may be present in certain embodiments of the
invention.
[0015] FIGS. 8 to 10 provide views of various positioning
mechanisms that are found in certain embodiments of the
invention.
[0016] FIGS. 11A to 11B provide different illustrations of an
experimental configuration described in the Experimental section,
below.
DETAILED DESCRIPTION
[0017] Methods and devices for selectively removing an agent from a
physiological site, e.g., a physiological efferent fluid collection
site, are provided. Aspects of the invention include fluid removal
(e.g., aspiration) devices having a fluid removal element and a
flow modulator positioned at a distal end of the fluid removal
element. The flow modulator is configured to converge intersecting
fluid flow paths into the fluid removal element. Also provided are
systems and kits for performing the subject methods. The subject
invention finds use in a variety of different applications,
including the selective removal of both therapeutic and diagnostic
agents from a variety of different physiological sites.
[0018] Before the present invention is further described, it is to
be understood that this invention is not limited to particular
embodiments described, as such may vary. It is also to be
understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to be
limiting, since the scope of the present invention will be limited
only by the appended claims.
[0019] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range, is encompassed within the invention.
The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges and are also
encompassed within the invention, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those
included limits are also included in the invention.
[0020] Certain ranges are presented herein with numerical values
being preceded by the term "about." The term "about" is used herein
to provide literal support for the exact number that it precedes,
as well as a number that is near to or approximately the number
that the term precedes. In determining whether a number is near to
or approximately a specifically recited number, the near or
approximating unrecited number may be a number which, in the
context in which it is presented, provides the substantial
equivalent of the specifically recited number.
[0021] Methods recited herein may be carried out in any order of
the recited events which is logically possible, as well as the
recited order of events.
[0022] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the present
invention, the preferred methods and materials are now
described.
[0023] All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited.
[0024] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. It is
further noted that the claims may be drafted to exclude any
optional element. As such, this statement is intended to serve as
antecedent basis for use of such exclusive terminology as "solely,"
"only" and the like in connection with the recitation of claim
elements, or use of a "negative" limitation.
[0025] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
Methods and Devices
[0026] As summarized above, aspects of the invention include
methods for removing an agent from a physiological site, such as a
physiological efferent fluid collection site, of a living subject.
By physiological efferent fluid collection site of a living subject
is meant a site in a living entity, where the site may be naturally
occurring or artificially produced (such as by surgical technique),
where fluid from at least two different sources or inputs combines
or flows into a single location. An example of a physiological
efferent fluid collection site is the coronary sinus, as
illustrated in FIG. 1A, and described in greater detail below.
[0027] In certain embodiments, the physiologic site is not a
physiologic efferent fluid collection site. For example, the site
may be a site of a vessel in which agent is administered upstream
of the site and then remove downstream of the agent introduction
site, such the agent injection and collection sites are in the same
anatomical vessel for a first vessel and a direct extension of the
vessel. Examples of embodiments where the physiologic site of fluid
collection is not an efferent fluid collection site are shown in
FIGS. 1B and 1C. In FIG. 1B, vessel 1 bifurcates into side branch 2
and side branch 3. An agent may be injected upstream of the
bifurcation, e.g., at point 4, and removed following bifurcation
from each side branch by devices 5 and 6. FIG. 1 shows a variation
in which vessel 1 is not bifurcated. Agent is introduced at
location 4, detected at position 7 and removed at position 8.
[0028] The subject is generally an animal, where in certain
embodiments the animal is a "mammal" or "mammalian." The terms
mammal and mammalian are used broadly to describe organisms which
are within the class mammalia, including the orders carnivore
(e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and
rats), lagomorpha (e.g. rabbits) and primates (e.g., humans,
chimpanzees, and monkeys). In certain embodiments, the subjects
(i.e., patients) are humans. In certain embodiments, the
physiological efferent fluid collection site is a vascular efferent
fluid collection site, where fluid from at least two different
vessels joins into a single vessel. In certain embodiments, the
vascular efferent fluid collection site is a cardiovascular fluid
collection site, where fluid from at least two different veins
joins into a single venous structure. In a specific embodiment of
interest, the cardiovascular efferent fluid collection site is the
coronary sinus. In yet other embodiments, as indicated above, the
efferent fluid collection site may be an artificially, e.g.,
surgically, produced, fluid collection site, e.g., a non-naturally
occurring fluid collection site produced by surgically joining two
or more vessels together, etc.
[0029] In practicing embodiments of the subject methods, a fluid
removal device, e.g., an aspiration device, is introduced into
(i.e., positioned at), a target site. The target site is at least
proximal to the physiological site, which may be an efferent fluid
collection site and for ease of illustration is now further
described as an efferent fluid collection site. By "at least
proximal to" is meant that the target site is either upstream or
downstream of the collection site, or the same as the collection
site, so long as placement of the aspiration element at the target
site provides for the desired removal of agent from the collection
site upon actuation of the aspiration element, as described in
greater detail below. In certain embodiments, the target fluid
removal site is at a distance of 40 mm or less from the efferent
fluid collection site, e.g., at a distance of 15 mm or less from
the efferent fluid collection site.
[0030] Aspects of the fluid removal, e.g., aspiration device,
include a fluid removal element, e.g., aspiration element, and a
flow modulator positioned at a distal end of the aspiration
element. For ease of description, the fluid removal element is
primarily referred to herein as an aspiration element. The flow
modulator is configured to converge intersecting fluid flow paths
into the aspiration element. By intersecting flow paths is meant
flow paths that are not parallel, where the non-parallel flow paths
may or may not intersect each other at a right angle. In certain
embodiment, the intersecting flow paths are the product of two or
more different tributary vessels into the efferent fluid collection
site. An example of intersecting flow fluid flow paths as produced
by two different tributaries of the coronary sinus is provided in
FIG. 1. As can be seen FIG. 1, coronary sinus 12 has two
tributaries 14 and 16 that provide for two intersecting flow paths
13 and 15 respectively. The intersecting flow paths intersect in
the coronary sinus as shown by 17. As can be seen in FIG. 1, the
intersecting flow paths intersect each other and result in
divergent flow paths as they leave the coronary sinus.
[0031] As the flow modulator is configured to converge intersecting
flow paths, intersecting flow paths are brought together or focused
onto a common region, in contrast to the divergent trajectory that
is observed in the absence of the flow modulator shown in FIG.
1.
[0032] FIG. 2A provides a view of the effect of a flow modulator on
the intersecting flow paths observed in a coronary sinus. In FIG.
2A, following the point of intersection of flow paths 13 and 15 at
region 17, the intersecting flow paths are focused by modulator 18
to converge in region 19.
[0033] The flow modulators employed in embodiments of the invention
may have any convenient configuration, so long as they operate to
converge (i.e., focus) intersecting flow paths onto a defined
region, such as the distal end of an aspiration element to which
the flow modulator is operatively coupled. In certain embodiments,
the distal end of the aspiration element is coupled to the end of
the of the flow modulator such that it is not in direct fluid
communication with the bounded space of the flow modulator. See
e.g., FIG. 2B. In FIG. 2B, aspiration catheter has opening 22 which
is positioned some distance from the end 24 of flow modulator 26.
Attachment elements 25 hold flow modulator 26 in position relative
to aspiration catheter 20 and openings 27 provide for fluid flow
out of flow modulator 26 when negative pressure is not present in
aspiration catheter 20. In the embodiment shown in FIG. 2B, the
distal end 22 of the aspiration catheter is coupled to the proximal
end 24 of the flow modulator in a manner such that the aspiration
catheter is not in direct fluid communication with the lumen of the
flow modulator. In certain embodiments, the distal end of the
aspiration element is not coupled to the end of the of the flow
modulator 26, but instead extends partway into the area defined by
the flow modulator, i.e., the lumen, e.g., as shown in FIG. 2C.
These different configurations can provide for different flow
configurations as shown in FIGS. 2D & 2E, where a particular
flow configuration may be desirable for a given application.
[0034] Following positioning of the aspiration element and flow
modulator at the target site, the aspiration device is activated
when the agent to be removed is at least predicted to be present in
the target site. Activation occurs in a manner effective to remove
fluid comprising the target agent from the subject. Embodiments are
characterized in that the agent is selectively removed from the
efferent fluid collection site. The flow modulator of the
aspiration device may be positioned at any convenient location, so
long as it serves to converge intersecting flow paths as desired.
In certain embodiments, the flow modulator is positioned at an
intersection of two or more tributaries of the physiological
efferent fluid collection site, e.g., where main (or axial) and
side (or radial) flow paths intersect.
[0035] As reviewed above, aspects of the invention include the
selective removal of agent from the efferent fluid collection site.
By "selectively removed" is meant that the subject methods remove
fluid from the target site in a manner that selectively or
preferentially removes fluid that is at least predicted to include
the agent, where the removed fluid is not returned to the body, at
least not without processing to remove the target agent present
therein. (In certain embodiments the removed fluid is simply
disposed of, such that the methods include a step of disposing of
the removed fluid, while in other embodiments the fluid is
processed (e.g., filtered) and then returned to the subject, as
reviewed in greater detail below). Depending on the particular
protocol and device employed, as described in greater detail below,
the fluid may be continuously collected at the fluid collection
site but not removed from the body unless it is at least predicted
to include agent, e.g., as occurs in those embodiments where fluid
is collected at the fluid collection site but immediately shunted
back to the subject if it is not at least predicted to include
agent. By "at least predicted" is meant that the bulk or majority
of the fluid removed from the site is fluid that is either
anticipated to include the agent, e.g., fluid in which the presence
of the agent is inferred, or fluid that is known to include the
agent, e.g., fluid in which the presence of the agent is detected.
Depending upon the particular embodiment of the invention being
practiced, in selectively removing fluid from the target fluid
collection site and subject, fluid may be removed from the site and
subject for a period of time which commences prior to when agent is
at least predicted to be in the site, and extend for a period of
time after agent is at least predicted to be in the site. In such
embodiments, the period of time during which fluid is collected
before and/or after agent is at least predicted to be in the site
is a fraction or portion of the total period of time during which
fluid is removed, typically being less than 50%, such as less than
25% including less than 10-15% of the total time period during
which fluid is removed.
[0036] In certain embodiments, the subject methods do not remove
all fluid from a target and efferent fluid collection site, but
just fluid that is at least predicted to include the target agent
of interest. In other words, in practicing the subject methods, not
all fluid from an efferent fluid collection site present over a
given period of time is removed, only fluid that is at least
predicted to include the target agent of interest that is to be
removed. Put another way, over a given period of time where fluid
that does and does not include the target agent flows through the
efferent fluid collection site and/or a target fluid collection
site, only fluid that is at least predicted, e.g., is anticipated
or known to include the agent, is removed from the site and
subject, while fluid that does not likely include the target agent
is preferentially not removed from the site and subject.
[0037] Another aspect of certain embodiments of the subject methods
is that, in certain embodiments, not all of the agent that is
administered prior to practice of the subject methods is removed
from the subject. In other words, only a portion of the
administered agent is removed from the host or patient by the
subject methods. By portion is meant at least about 20%, usually at
least about 50% and more usually at least about 70% of the
administered agent is removed by the subject methods, where in
certain embodiments, the portion removed is at least about 75%, at
least about 80%, at least about 90% or more. However, as not all of
the agent is collected during practice of embodiments of the
subject methods, in certain embodiments at least 1% of the
originally administered agent remains in the subject or patient,
such as at least about 5% or at least about 10%.
[0038] Agent is selectively removed from the target site, which may
or may not be the efferent fluid collection site, according to the
subject methods by removing, e.g., aspirating, fluid from the
target site and subject, substantially only when the target agent
is at least predicted to be present in the target site, as
described above. As such, when agent is at least predicted to be
present in the target site, fluid is removed from the site and
subject. Conversely, in certain embodiments when agent is not
predicted to be present in the site, fluid is not removed at least
from the subject, and in certain embodiments not from the site.
Accordingly, in certain embodiments, upon detection or anticipation
of agent in the fluid collection site fluid is removed or aspirated
from the site and subject, while when the target agent is not
detected or anticipated to be present in the site, fluid is not
removed from the site, with the exception of a short period of time
before and/or after the time when agent is at least predicted to be
in the target site, as described above.
[0039] In certain embodiments, fluid is selectively removed by
actuating a fluid removal element, e.g., aspiration device, such as
the devices described below, a defined period of time following
administration of the agent to the subject, e.g., an absolute
preset period of time, a period of time as defined by a
physiological metric, e.g., heart beat, etc.
[0040] In certain embodiments, the methods include a detection
step, where a procedure relevant parameter is detected using an
appropriate sensor (i.e., detector) element. A variety of different
procedure relevant parameters may be detected, as desired. Such
parameters include, but are not limited to: the agent itself (which
may be detected both directly and/or indirectly), flow dynamic,
e.g., hemodynamic parameters, anatomical parameters, etc. A variety
of sensors may be employed, including but not limited to: impedance
sensors, ultrasound sensors, Doppler sensors, optical sensors,
etc.
[0041] In certain embodiments, the methods include a step of
detecting one or more fluid flow parameters, such as hemodynamic
parameters. For example, fluid flow may be assessed at various
locations of an efferent fluid collection site during a given
protocol. With respect to the coronary sinus, fluid flow may, for
example, be assessed at the flow outlet of the flow modulator to
the aspiration element (e.g., to provide activation efficiency of
aspiration) and/or at the ostium (OS) of the coronary sinus (e.g.,
for assessing reflux from the right atrium). A variety of different
types of flow dynamic sensors may be employed, as desired, where
such sensors include deflection sensors, thermal sensors, sensors
of oxygen contents e.g., that provide an assessment of flow
direction or orifice of a tributary during device insertion,
etc.
[0042] In certain embodiments, the methods include a step of
detecting anatomical structures or features, e.g., to assist in
proper placement of the device at the target site. For example,
detectors for assessment of branching points of tributaries of
interest (e.g., middle cardiac vein, posterior vein of left
ventricle, lateral vein of left ventricle, and other vascular
tributaries) may be employed (e.g., to aid in axial positioning of
the device at the target site). Examples of such detectors include
flex detectors (e.g., as described in United States Published
Application No. US-2006-0173365-A1), in which bending of a material
causes signal generation that can be used to determine when the
structure passes a certain anatomical feature of interest. Another
type of detector that may be employed for this purpose is an EKG
detector, which uses the distinct EKG signatures associated with
anatomical transition points, such as the entry to the coronary
sinus, to determine location of the catheter in the vessel and aid
in placement at the desired location.
[0043] Additional detectors may be employed, where desired, to
provide data which can be employed to modulate operating parameters
of the device during aspiration, e.g., aspiration rates, etc. For
example, EKG activity may be detected to obtain reference
time-points for adapting aspiration rates to the instantaneous flow
inside the target site, as the flow in the target site may
fluctuate as various time points during the EKG cycle. In addition,
pressure detectors, e.g., for assessment of vacuum efficiency or
for detecting CS-pressure signature during device insertion, may be
employed, e.g., to provide data which may be used to modulate
evacuation rates. Likewise, flow detectors for assessment of
baseline flow rate may also be employed for similar purposes.
[0044] In certain embodiments, the methods include a step of
detecting the presence of target agent in the site and then
removing fluid, and agent present therein, from the site in
response to detection of the presence of target agent in the site.
As reviewed in greater detail below, the presence of the agent may
be detected directly or indirectly. Typically, when agent is no
longer detected in the efferent fluid collection site, the methods
stop removing fluid from the site. Thus, fluid is only removed from
the efferent fluid collection site and subject over a time period
that substantially overlaps the period in which the target agent is
present in the efferent fluid collection site.
[0045] In practicing these embodiments of the subject methods, the
agent may be detected in the fluid collection site using a number
of different protocols. In certain embodiments, agent is visually
detected by a skilled operator, who then removes fluid in response
to visualizing agent, e.g., according to the protocols described
below, present in the fluid collection site. In yet other
embodiments, agent detection devices that are operatively connected
to a fluid removal device are employed, where a signal from the
detector that agent is present in the fluid collection site
automatically actuates a fluid removal device, e.g., aspiration
unit. Representative embodiments of devices that may be employed in
such embodiments are described in greater detail below.
[0046] In certain embodiments, the system includes a detector
(i.e., sensor) component, e.g., for detecting the agent of interest
(or a proxy therefore). The agent of interest may be detected using
a number of different approaches. In certain embodiments,
properties of the agent itself are detected. For example, specific
binding of the agent may be employed, e.g., using a binding event
sensor; optical/photometric approaches for detecting the agent,
e.g., reflectance, transmission, evanescence, etc., may be
employed; physical, e.g., viscosity, changes caused by the agent
may be employed; electrical, e.g., conductivity, changes caused by
the agent may be employed; radioactive, e.g., radiosorbance,
approaches may be employed; fluorescence changes caused by the
agent may be employed; acoustic, e.g., ultrasonic: echogenicity,
scattering, etc. changes caused by the agent may be employed,
etc.
[0047] In certain embodiments changes in the fluid caused by the
presence of the agent are employed to detect the presence of the
agent. Changes of interest in a given fluid include, but are not
limited to: changes in number of blood cells per volume; changes in
optical properties; changes in chemical properties; changes in
physical properties (density, hematocrit, viscosity); changes in
hemodynamic properties (velocity); changes in overall imaging
properties of blood (ultrasonic, radioactive, radiosorbent,
fluorescent, etc.
[0048] To aid in the detection of the agent, in certain embodiments
the agent will be one that is labeled with a detectable label,
e.g., agent that is has been labeled with a detectable label prior
to its introduction into the patient. The agent may be directly
labeled with the detectable label, or associated with a detectable
label such that the agent is indirectly detectable in that
detection of the label also indicates the presence of agent which
is presumed or inferred to be within the vicinity of the label. The
nature of the label may vary, and may be a radio label, fluorescent
label, chromogenic label (e.g., that has a pigment detectable in
the optically visible spectrum), etc.
[0049] In certain embodiments, the pressure of the target site
and/or efferent fluid collection site (which may or may not be the
same locations, as described above) and or the tributaries thereof,
including a subset of the tributaries thereof, may be modulated,
e.g., reduced, in order to achieve the desired collection of agent
from the host. The manner in which the pressure may be modulated
may vary depending on the particular device employed and manner in
which it is implemented, where representative devices and protocols
capable of pressure modulation of the target/efferent fluid
collection site are described in greater detail below. By
modulating the pressure in this manner, one can reduce the pressure
within the collection site sufficiently to improve the efficacy of
removing the desired agent without causing collapse of the
tributaries of the efferent fluid collection site, resulting in a
better favorable outcome of the method.
[0050] In certain embodiments, devices that include a shunting
element, be it a passive or active shunting element, are employed
in a manner that modulates the pressure of the target site and/or
efferent fluid collection site, as desired. Alternatively and/or in
addition thereto, one can use of a pressure sensor within the fluid
collection site. The output from such a sensor may be used to
optimize the maintenance of the pressure in the collection site so
that it is reduced sufficiently in order to increase the likelihood
of higher flow to that region from those tributaries that have
alternative paths, without causing the collapse of such
tributaries.
[0051] In certain embodiments, an extension of an aspiration lumen
of the device employed is extended selectively into one or more
tributaries in order to prevent their collapse during aspiration
and to extend the volume from which fluid is aspirated.
Alternatively, rather than using a lumen to structurally support
the tributaries, a temporary or permanent stent could be introduced
to those tributaries prior to aspiration.
[0052] In certain embodiments, a specific pattern of aspiration
rates that compensates for the delay time between the detection of
the desired agent and the activation of the aspiration mechanism is
employed. For example, in certain embodiments, there will be a
small but finite delay in time between when the agent enters the
fluid collection site and when the aspiration mechanism begins to
aspirate fluid from the site. During this time delay, some of the
fluid containing the agent may have already passed the region from
which aspiration normally occurs at the distal portion of the
aspiration lumen, thus potentially reducing the efficacy of
retrieving the agent. However, by having a higher rate of
aspiration for the early portion of the period in which aspiration
occurs, as compared to a rate that more closely resembles the
normal physiologic rate of flow within the collection site, e.g.,
where the higher aspiration rate is 2-fold greater, such as 5-fold
or 10-fold greater or more, one can cause that fluid which has
already passed the region from aspiration to change direction and
return to the aspiration ports. Once this initial period of a
higher rate of aspiration has expired, the aspiration rate could
then occur at a lower rate which more closely approximates the
normal physiologic rate of flow within the collection site, as
desired. Varying aspiration rates maybe required at sites where
inflow from tributaries follows a cyclical patterns. A typical
example is the inflow from the middle cardiac vein into the
coronary sinus, where peaks are registered during systole, and lows
during diastole. For this purpose, EKG triggering of aspiration may
be employed.
[0053] In some embodiments, more than one kind of detector is
employed to determine the aspiration parameters and time period.
For example, in order to ensure that the leading edge of the agent
is successfully aspirated, the activation of the aspiration
mechanism may be activated by a counter that counts a conservative,
pre-selected number of QRS complexes on an EKG after the beginning
of injection of the agent, while the trigger to deactivate the
aspiration mechanism may be derived from an optical sensor that can
recognize when there is no longer any more agent within the fluid
being aspirated. Alternatively, inputs from more than one detector
can be used in direct combination with each other to determine the
aspiration parameters. For example, due to cardiac motion in the
region of a fiber optic based sensor, and/or variations in the rate
of flow of the fluid in the region of the sensor, the signal
produced may vary in a pattern that is reflective of the cardiac
cycle, regardless of whether or not the agent to be detected is
present, thus producing a noisy signal. In such a case, the
fidelity of the sensor may be augmented by using a filtering
algorithm that uses the input from an EKG signal to filter the
signal produced by the optical detector. By compensating for
changes to the output of the optical detector that are due to the
cardiac cycle, it may be easier to more accurately characterize the
concentration of the agent to be removed in the region of the
detector. Any of the detectors mentioned below may be suitably used
in combination with each other to further optimize the detection
process and/or the efficacy of the aspiration controller. In
certain embodiments, a feedback from the agent injection system can
be incorporated into the signal processing algorithm, which
ultimately leads to commencement of aspiration.
[0054] Practice of the subject methods results in selective removal
of an agent from a fluid collection site and subject (also referred
to herein as patient or host), where the amount of agent removed
is, in certain embodiments, a substantial portion of (but not all
of in certain embodiments) the agent that is present in the
subject, as described above.
[0055] In certain embodiments, the fluid that is removed from the
subject or patient may be treated extracorporally, e.g., to remove
or neutralize the agent, and then reintroduced into the subject,
e.g., where it is desired to minimize the ultimate or final volume
of fluid, e.g., blood, that is removed from the subject in a given
procedure. For example, where the fluid removed from the subject is
blood, the removed blood may be processed with a blood filtering
device to remove the agent from the blood, and the processed blood,
or at least a component thereof (such as red blood cells) be
returned to the patient. Examples of fluid, e.g., blood, processing
devices include, but are not limited to: the Cell Saver.RTM. device
(available from Haemonetics); autoLog (available from Medtronic);
and the like.
[0056] As such, the subject methods may include a step of
transferring the harvested fluid into a recirculating system to be
reintroduced into the body (as described in U.S. Pat. No.
5,925,016, the disclosure of which is herein incorporated by
reference). The recirculating system may incorporate mechanisms to
separate the substantially undesirable components from the
substantially desirable components. Such a system may incorporate a
filter, a centrifugal separator, flow cytometry, apheresis or other
similar apparatuses. The aspiration mechanism may incorporate fluid
characterization elements by which aspirated fluid may be
characterized, either quantitatively or qualitatively.
[0057] Accordingly, in certain embodiments the subject may be one
in which it is desired to keep blood loss at a minimum, e.g., the
patient may suffer from coronary artery disease, chronic anemia,
etc. Extracorporeal processing and subsequent reinfusion of the
treated fluid allows for the reintroduction of the desirable
components as an autologous transfusion. Centrifugal mechanisms,
filter-based systems, dialysis membranes and cell-washing
mechanisms are examples of some functional components that can be
employed for this purpose.
[0058] The methods may be carried out using any convenient
system/device, where in certain embodiments, catheter based
systems/devices are of interest. Embodiments of aspiration devices
and systems thereof for use in practicing the subject invention are
reviewed in greater detail in the following section.
[0059] As summarized above, the aspiration devices employed in
methods of the invention include an aspiration element having a
proximal and distal end, and a flow modulator present at the distal
end of the aspiration element.
[0060] With respect to the aspiration element, this element may
include one or more aspiration lumens, where the aspiration
lumen(s) is constructed or configured in such a manner to be
introduced into the target collection site, e.g., efferent fluid
collection site or a site proximal thereto, e.g., via a body
conduit such as the venous vasculature, so that the distal end of
the lumen can be positioned in the target site for collection of
the introduced medium. In certain embodiments where the target
efferent fluid collection site is a cardiovascular efferent fluid
collection site, e.g., as in the case of retrieving compound-laden
fluid from the coronary sinus, there may be a catheter with a
length appropriate for introduction through either a brachial,
subclavian, jugular or femoral access site to be advanced to the
coronary sinus, likely over a guidewire or similar element, for
percutaneous delivery. In these embodiments, the aspiration lumen
is a catheter device, having dimensions sufficient to be introduced
into the efferent fluid collection site via a vascular, e.g.,
venous route, where such dimensions are known and readily
determined by those of skill in the art.
[0061] In certain embodiments, the aspiration lumen has more than
one diameter along its length. For example, in order to more easily
to enter or approach a collection site, the distal portion of the
aspiration catheter is of a first diameter such that the distal
portion fits within the geometric constraints of the anatomy of the
collection site. In order to reduce the resistance to flow along
the entire length of the aspiration lumen, the aspiration lumen has
a second, larger diameter for one or more proximal segments of the
aspiration lumen. In some cases where a high degree of flow may be
required in order to successfully aspirate all the fluid that
enters the collection site, such a configuration helps to reduce
the total resistance of the lumen, which is proportional to the
fourth power of the radius and is thus very sensitive to lumen
diameter.
[0062] In certain embodiments, the inner surface of the lumen may
be shaped, e.g., to promote aspiration along the length of the
element. For example, the inner surface may have a spiral
configuration, e.g., a spiral ridge, on the inner surface of the
lumen.
[0063] The aspiration lumen is, in certain embodiments,
specifically constructed to be non-occluding. As such, the
aspiration lumen of these embodiments does not include an occlusive
element, e.g., a balloon or other element designed to occlude a
vessel or conduit. As such, the subject devices of these particular
embodiments are occlusive element-free devices.
[0064] Positioned at the distal end of the aspiration element is a
flow modulator. An example of a flow modulator is depicted in FIG.
2A. In FIG. 2A, the flow modulator is configured so that, when
deployed, it produces a flared end at the proximal end of the
aspiration element. Not shown in the structure of FIG. 2A are flow
shunt elements which make up a flow outlet and provide for an exit
for fluid flow when aspiration is not occurring.
[0065] Another example of a flow modulator of interest is one that
includes an expandable frame of two or more longitudinal elements.
FIG. 3 provides a view of an embodiment of such a flow modulator.
In FIG. 3, an aspiration device that includes an aspiration element
(in the form of an aspiration catheter) 32 and a flow modulator
having an expandable frame 36 at its distal end is positioned in
the coronary sinus. The region where the flow modulator is joined
to the distal end of the aspiration element is referred to herein
as the "flow outlet" 40. The expandable frame includes two or more
longitudinal elements 33, where the embodiment shown in FIG. 3 has
6 longitudinal elements. The longitudinal elements may be any
convenient structure, including a resilient monofilament, which may
fabricated from a material such as Nitinol, stainless steel,
cobalt-chromium alloys, and the like.
[0066] While the overall frame shape may have any convenient
configuration, in certain embodiments the frame shape is
cylindrical or substantially cylindrical. Of interest are frame
shapes that have tapered (i.e., infundibular) shape at their
proximal end, which shape can provide for certain advantages, e.g.,
reversal of unfavorable anatomical tapering, such as venous
tapering. Also, when a centering mechanism for the detector is
employed with such configurations, this configuration can ensure
that the centering mechanism positions the detector at a desired
location in the flow modulator so that optimal detection can be
achieved.
[0067] Positioned between the longitudinal elements of the flow
modulator of FIG. 3 is an impermeable membrane 34. The impermeable
membrane is positioned between two or more longitudinal elements,
including all of the longitudinal elements as shown in FIG. 3. The
impermeable membrane 34 may be fabricated from any convenient
material, including but not limited to polyurethane, polyester,
polyethylene and other polymer-based materials with a certain
degree of elasticity, and the like. While the membrane may define a
variety of configurations, in certain embodiments such as the one
shown in FIG. 3, the impermeable membrane is configured to produce
an asymmetric fluid barrier upon expansion of the expandable frame.
By asymmetric is meant that the membrane does not define a bounded
region of uniform axial length. The membrane 34 is bounded at the
distal end by flow inlet 38 and at the proximal end by flow outlet
40.
[0068] In practicing the invention, following positioning of the
distal end of the aspiration device (that includes the aspiration
element a flow modulator) at the target site, the flow modulator is
deployed, e.g., by expanding the frame at the target site (which
includes the site of intersection of the fluid flow paths).
Deployment may be by passive or active mechanism, as desired. For
example, the expandable frame may be fabricated from a shape memory
material, e.g., Nitinol, shape-memory and/or super-elastic
materials, which is compressed during delivery and then the
compressive force on the frame is removed to deploy the frame.
[0069] The embodiment shown in FIG. 3 includes an aspiration
element and flow modulator which are configured so that fluid flows
past the aspiration element when the aspiration element is not
activated. In the embodiment shown in FIG. 3, the flow modulator
includes a flow outlet 40 positioned downstream of membrane at the
coupling region of the expandable from and the distal end of the
aspiration element. When the aspiration device is not activated,
e.g., when agent is not at least predicted to be present at the
target site, fluid flows out of the flow outlet.
[0070] The configuration of the membrane in the embodiment of FIG.
3 provides for the desired convergence of fluid flow lamina that
originate in both axial and sidewise (i.e., radial) directions, as
illustrated in FIG. 4A. As shown in FIG. 4A, the axial flow lamina
from the main vessel tributary and the sidewise or radial flow
lamina from the side branch tributary intersect within the region
bounded by the impermeable membrane and are then converged or
focused onto the distal end of the aspiration catheter 32. In this
way, the flow modulator converges the intersecting flow paths or
lamina of the main and side vessels entering the efferent fluid
collection site, e.g., coronary sinus, onto the distal end of the
aspiration catheter.
[0071] FIGS. 4B to 4D illustrate the function of a device according
to an embodiment of the invention. As illustrated in these figures,
the flow inside a blood vessel is typically phasic, with
alternating phases of high and low flow. Assuming constant
aspiration rates through the catheter, during periods of high flow
rate as illustrated in FIG. 4B, the flow (a) enters the flow
modulator tip of catheter, and is predominantly captured by
aspiration (d). If the flow rates are higher than aspiration rates,
the flow would exit (b) the flow modulator without being captured
during this phase. In certain instances, the action of aspiration
causes downstream flow to reverse following aspiration/pressure
gradient. During period of low flow as illustrated in FIG. 4C, the
slow/still flow (a, b) is mobilized and captured (d) as a result of
the aspiration gradient. Assuming that aspiration rates are higher
than flow rates during this phase, a portion of the down-stream
flow can be reversed (c) and captured by aspiration, thus
compensating for flow that has escaped aspiration during high-flow
phase (FIG. 4B, item b). During periods of non-aspiration as
illustrated in FIG. 4D, the flow passes through the flow modulator,
and exits it without being captured by the aspiration catheter.
[0072] In certain embodiments, the flow outlet between the flow
modulator and aspiration element may include features that provide
for control over fluid flowing through the flow outlet. In certain
embodiments, the flow outlet is configured to allow bidirectional
fluid flow, as shown in FIG. 5A. In certain embodiments, the flow
outlet is configured to allow for unidirectional fluid flow, as
shown in FIG. 5B. Where desired, fluid flow through the flow
outlet, either unidirectional or bidirectionally, may be detected.
Any convenient flow detection protocol may be employed, including
the approach shown in FIG. 5C where a check valve 55 is present at
the flow outlet, where the valve allows for fluid outflow only.
[0073] FIGS. 6A and 6B provide an illustration of another type of
flow modulator that may be employed in certain embodiments of the
invention. In FIGS. 6A and 6B, the flow modulator is non-flow
through expandable flow modulator. A catheter 61 includes an
expanding tip 62, which acts as a non-flow through flow modulator.
The catheter 61 also incorporates an inner channel 63 for guide
wire to facilitate over-the-wire (OTW) placement of the catheter
61. The catheter also incorporates at least one optical fiber 64
which terminates in the vicinity of the flow modulator. In one
embodiment, at least one end of the expanding flow modulator 62 is
axially movable against said inner channel 63. FIG. 6B provides a
view of the device shown in FIG. 6A, where the flow modulator is
collapsed and retracted into the lumen of the aspiration catheter,
e.g., during placement of the catheter and/or when the catheter is
not in use.
[0074] As summarized above, in certain embodiments, the methods may
include a detection step, where a physiologic parameter and/or the
agent and/or a physiological (e.g., anatomical) structure, etc., is
detected in the efferent fluid collection site. Depending on the
nature of the item to be detected, e.g., the physiologic parameter,
the agent, etc., a variety of different types of sensors or
detectors may be employed. Detectors of interest include, but are
not limited to: fiber-optic based sensors, temperature sensors,
acoustic sensors, pH detectors, capacitance-based detectors, fluid
velocity detectors, conductivity detectors and detectors able to
detect changes in ferro-electromagnetism or magnetic susceptibility
(see e.g., Blood, 1 Jan. 2003, Vol. 101, No. 1, pp. 15-19) and the
like. Detectors of interest include those detectors described in
published United States Application Nos. 20050124969 and
20040254523, the disclosures of various detectors described therein
are herein incorporated by reference.
[0075] The sensors or detectors may be associated with the
aspiration device itself, e.g., be present on the flow modulator,
the aspiration element, etc., or may be positioned in the efferent
fluid collection site using a distinct or separate device.
[0076] In certain embodiments, the methods include detection of
fluid flow at the efferent fluid collection site. For such methods,
any convenient flow detector may be employed. In certain
embodiments, the flow detector is a hemodynamic sensor, which
sensor is provided at the efferent fluid collection site. One type
of a hemodynamic sensor is based on temperature, where a heating
element can heat the fluid in first location and temperature
sensors positioned at fixed locations upstream and downstream of
the heating (or cooling element) element can detect changes in the
temperature of the fluid medium flowing past them and from the
detected changes determine direction of fluid flow. An embodiment
of such a sensor is provided in FIG. 7A. Alternatively, the flow
sensor could comprise a sensor material that is moved by fluid flow
and generates signals in response to movement that can be employed
to determine fluid flow. Such a sensor is depicted in FIG. 7B.
[0077] In certain embodiments, the detector is a detector
configured to detect the presence of the agent to be removed in the
efferent fluid collection site. As reviewed published United States
Application Nos. 20050124969 and 20040254523, agents may be
detected directly or indirectly. For example, an agent may be
directly detected by detecting its optical or other properties.
Alternatively, an agent may be indirectly detected by detecting
changes that occur in response to presence of the agent in the
efferent fluid collection site, e.g., changes in optical properties
of the fluid, changes in physiology of the efferent fluid
collection site, etc. In certain embodiments, a fiber optic
detector is employed, which detects the presence of the agent,
e.g., contrast agent, in the fluid when the agent is present at the
efferent fluid collection site.
[0078] In certain embodiments, the detector is one that is
associated with the aspiration device and, as such, is introduced
into the efferent fluid collection site with the aspiration device.
In some embodiments, the detector is introduced to the efferent
fluid collection site through the aspiration element, where the
detector is a fiber optic cable introduced through the aspiration
element.
[0079] In certain embodiments, it is desirable to be able to
precisely position the detector at a particular location in the
efferent fluid collection site. Precise positioning of the detector
in the target site can be accomplished using any convenient
protocol. In certain embodiments, the aspiration device includes a
centering mechanism that works to position the detector in the
target site. An example of such a centering mechanism is shown in
FIG. 8. In the device shown in FIG. 8, an articulation element 82
coupled to the wall of the flow modulator 84 by positioning
mechanism 86 such that is positioned near the distal end of the
detector catheter 88 serves to position the detector in the center
of the flow modulator 84 at a desired location. An alternative
embodiment is shown in FIG. 9. In the device shown in FIG. 9, an
articulation element 92 coupled to the wall of the aspiration
catheter 94 and positioned near the distal end of the aspiration
catheter 94 serves to position the detector and detection catheter
88 in the center of the flow modulator at a desired location. In an
alternative embodiment, the detector element is present on a
steerable element, e.g., a steerable catheter, such that no
distinct centering mechanism is required. Such an embodiment is
shown in FIG. 10. Other embodiments of interest include those where
the detector is incorporated into the wall of the aspiration
element and embodiments where the detector is a separate element
which can be closely associated with the device to provide for the
desired placement, e.g., where it is configured to be passed
through an outflow element of the device to be positioned in the
desired location.
Systems
[0080] Also provided are systems for use in practicing the subject
methods, where the systems include an aspiration device for
selectively removing agent from the efferent fluid collection site,
such as the representative devices described above, and may
optionally include one or more additional components that find use
in practicing the subject methods, e.g., detectors, agent
introducers, data recorders, etc. In certain embodiments, the
system includes an aspiration controller and aspiration mechanism
operatively linked to an aspiration lumen which is introduced into
the subject (body), as well as a number of additional/optional
components, such as an injection/delivery system for introducing
agent into the body at a site upstream of the target efferent fluid
collection site, one or more detector elements for detecting the
presence of agent in the efferent fluid collection site, and an
aspiration recorder/display element for recording data (e.g., fluid
flow data, etc.) and displaying the same to the operator. Of
interest are the systems described in published United States
Application Nos. 20050124969 and 20040254523, the disclosures of
which systems described therein modified to include aspiration
devices of the present invention are herein incorporated by
reference.
Utility
[0081] The subject invention finds use in a wide variety of
different applications, including both diagnostic and therapeutic
applications. Of interest is the use of the subject methods and
devices to selectively remove from a subject a locally administered
diagnostic or therapeutic agent, so that the host or subject is not
systemically exposed to the diagnostic or therapeutic agent.
[0082] In certain embodiments, the subject methods are employed to
selectively remove a locally administered diagnostic agent, such
that the diagnostic agent is only contacted with a limited region
or portion of the host to which it is administered, e.g., a
specific organ or portion thereof. A common example of such a
compound is radio-opaque dye. Iodinated forms of such a dye are
used routinely during catheter-based interventional procedures such
as coronary, renal, neurological, angioplasty, and peripheral
arteriography. The iodine component has a high absorption of x-rays
and therefore provides a contrast medium for the radiological
identification of vessels when introduced within an upstream
artery. However, the use of such dyes is known to have potential
toxic effects depending on the specific formulation, including
direct injury to renal tubule cells, endothelial injury,
bronchospasm, inflammatory reactions, pro-coagulation,
anti-coagulation, vasodilation and thyrotoxicosis.
[0083] Another application of the subject invention is in the
selective removal from a patient of a locally administered
therapeutic agent, where representative therapeutic agents or
materials that may be introduced locally for desired effects but
whose direct or other effects would be undesired elsewhere include
vasoactive agents, cytotoxic agents, genetic vectors, apoptotic
agents, anoxic agents (including saline), photodynamic agents,
emboli-promoting particles or coils, antibodies, cytokines,
immunologically targeted agents and hormones. Additional agents of
interest include, but are not limited to: cells, enzymes,
activators, inhibitors and their precursors, as well as sclerosing
agents, anti-inflammatories, pro-inflammatories, steroids and
osmotic agents, and the like. As such, another representative
application of the subject methods is to determine the amount of
agent retained at a local area or region of a subject upon local
administration of the agent to the subject. For example, where a
therapeutic agent is locally administered to a region or location
of a subject, e.g., an organ, and blood carrying the agent is
selectively removed from the subject according to the subject
methods, the amount of agent in the collected blood can be used to
determine the amount of agent that was retained by the local region
or area, e.g., organ, of the subject. As such, in those cases where
the present invention is used to retrieve a diagnostic or
therapeutic agent for which a portion of that agent desirably
resides in the region into which it is delivered, and the portion
of the agent collected from the collection represents an amount of
the agent that did not remain resident in that region, the subject
methods may be employed to estimate the effective dosage of the
agent. For example, in the localized delivery of a chemotherapeutic
agent via the afferent branches of a targeted tumor, the present
invention is capable of collecting some of the chemotherapeutic
agent after it passes through tumor bed, but before it is able to
enter into the systemic circulation, thus minimizing its side
effects. The difference between the amount of agent injected and
the amount of agent that is retrieved by the present invention
represents the sum of the amount of agent that was successfully
incorporated into the tumor and the amount of agent that escaped to
the systemic circulation. If a goal of the localized delivery of
the chemotherapeutic agent is to attempt to incorporate a given
dosage of the agent into the tumor, it is possible to use the
present invention to better estimate how much of the delivered
agent was successfully incorporated into the tumor by estimating
how much of the agent was retrieved in the collection site.
Alternatively, the present invention can be used to allow higher
dosage application of agent, the majority of which can then be
detected and removed at efferent collection site of the target
organ. If a higher than expected amount of agent was retrieved in
the collection site, than a substantial portion of the agent was
not successfully incorporated into the tumor and this may direct
the physician to deliver more agent to the tumor, or consider
alternative strategies for treatment. The higher the efficacy of
the present invention is in terms of retrieving the agent, the more
accurate the estimate of the amount of agent successfully delivered
to the site will become.
Kits
[0084] Also provided are kits for use in practicing the subject
methods, where the kits may include one or more of the above
devices, and/or components of the subject systems, as described
above. As such, a kit may include a device, such as a catheter
device, that includes an aspiration lumen, aspiration mechanism and
aspiration mechanism controller, as described above. The kit may
further include other components, e.g., guidewires, etc., which may
find use in practicing the subject methods.
[0085] In addition to above mentioned components, the subject kits
typically further include instructions for using the components of
the kit to practice the subject methods. The instructions for
practicing the subject methods are generally recorded on a suitable
recording medium. For example, the instructions may be printed on a
substrate, such as paper or plastic, etc. As such, the instructions
may be present in the kits as a package insert, in the labeling of
the container of the kit or components thereof (i.e., associated
with the packaging or subpackaging) etc. In other embodiments, the
instructions are present as an electronic storage data file present
on a suitable computer readable storage medium, e.g. CD-ROM,
diskette, etc. In yet other embodiments, the actual instructions
are not present in the kit, but means for obtaining the
instructions from a remote source, e.g. via the internet, are
provided. An example of this embodiment is a kit that includes a
web address where the instructions can be viewed and/or from which
the instructions can be downloaded. As with the instructions, this
means for obtaining the instructions is recorded on a suitable
substrate.
[0086] The following example is offered by way of illustration, and
not by way of limitation.
EXPERIMENTAL
I. Aim
[0087] The aim of the present experiment is to assess patterns of
flow at the proximal coronary sinus in a glass model of the human
heart. Specifically, the current experiment is designed to map the
proximal coronary sinus in terms of flow paths of CS versus
MCV.
II. Methods
[0088] For nomenclature purposes, CS segments upstream to MCV will
be referred to as great cardiac vein (GCV). The flow from the GCV
would naturally extend into and form the main CS flow (down-stream
from MCV).
[0089] A glass model simulating the anatomy of the human heart was
utilized to test the pattern of flow in the proximal CS. As a test
medium, the glass heart model (GHM) was filled with sheep blood. A
human-equivalent blood circulation was created utilizing a
peristaltic flow pump at a flow rate of 2.3 L/min, leading to a
realistic human CS flow of approximately 4 mL/sec.
[0090] For purposes of mapping flow paths of GCV, and MCV, a
fiberoptic flow detector was used, which can be inserted into the
proximal segments CS of GHM. Additionally, a method was developed
to reliably position the detector at various positions inside the
proximal CS to map flow paths of GCV and MCV.
[0091] When mapping the flow path of a specific tributary at a
predetermined CS-position, radiographic contrast agent was injected
into the tributary, and an input from the detector was registered.
Absence of signal from the detector would indicate absence of
agent's flow at the corresponding CS-position.
III. Summary of Result
[0092] FIGS. 11A and 11B represent the CS of the GHM with its two
main tributaries (MCV, and GCV). Also represented in FIGS. 11A and
11B are the testing positions of the detector. The detector was
positioned in the proximal segment of the coronary sinus,
specifically at or around the merging point of MCV, and proximal
(=upstream) thereof.
Mapping flow of the GCV: Detection signals of GCV flow at various
positions inside prox. CS revealed that GCV flow maintains an
axial, straight flow toward the Os of CS, despite intersecting MCV
flow.
[0093] Mapping flow of the MCV: Detection signal of the CS flow at
various positions inside prox. CS revealed that MCV flow projects
through GCV flow, and lands on the contralateral CS-wall. The MCV
flow would then slows down, is deflected by the GCV/CS flow, and
would flow eccentrically in axial direction toward the Os of
CS.
D. Conclusion
[0094] At the proximal coronary sinus, flow mapping studies
revealed that MCV flow intersects through (axial) GCV flow until it
hits the contralateral wall of the CS.
[0095] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is readily apparent to those of ordinary skill
in the art in light of the teachings of this invention that certain
changes and modifications may be made thereto without departing
from the spirit or scope of the appended claims.
[0096] Accordingly, the preceding merely illustrates the principles
of the invention. It will be appreciated that those skilled in the
art will be able to devise various arrangements which, although not
explicitly described or shown herein, embody the principles of the
invention and are included within its spirit and scope.
Furthermore, all examples and conditional language recited herein
are principally intended to aid the reader in understanding the
principles of the invention and the concepts contributed by the
inventors to furthering the art, and are to be construed as being
without limitation to such specifically recited examples and
conditions. Moreover, all statements herein reciting principles,
aspects, and embodiments of the invention as well as specific
examples thereof, are intended to encompass both structural and
functional equivalents thereof. Additionally, it is intended that
such equivalents include both currently known equivalents and
equivalents developed in the future, i.e., any elements developed
that perform the same function, regardless of structure. The scope
of the present invention, therefore, is not intended to be limited
to the exemplary embodiments shown and described herein. Rather,
the scope and spirit of present invention is embodied by the
appended claims.
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