U.S. patent application number 16/406646 was filed with the patent office on 2019-08-29 for device and method for the ablation of fibrin sheath formation on a venous catheter.
This patent application is currently assigned to AngioDynamics, Inc.. The applicant listed for this patent is AngioDynamics, Inc.. Invention is credited to William C. Hamilton, JR., Eamonn Hobbs.
Application Number | 20190262580 16/406646 |
Document ID | / |
Family ID | 41431955 |
Filed Date | 2019-08-29 |
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United States Patent
Application |
20190262580 |
Kind Code |
A1 |
Hobbs; Eamonn ; et
al. |
August 29, 2019 |
Device and Method for the Ablation of Fibrin Sheath Formation on a
Venous Catheter
Abstract
An indwelling venous catheter and method capable of destroying
undesirable cellular growth is provided. The catheter includes a
shaft having at least one lumen and adapted to be placed inside a
vein for long term use. A plurality of electrodes are positioned
near a distal section of the shaft and are adapted to receive from
a voltage generator a plurality of electrical pulses in an amount
sufficient to cause destruction of cells in the undesirable
cellular growth that have grown around the shaft. In one aspect of
the invention, a probe is configured to be removably insertable
into the at least one lumen and the electrodes are positioned near
the distal section of the probe.
Inventors: |
Hobbs; Eamonn; (Cleverdale,
NY) ; Hamilton, JR.; William C.; (Queensbury,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AngioDynamics, Inc. |
Latham |
NY |
US |
|
|
Assignee: |
AngioDynamics, Inc.
Latham
NY
|
Family ID: |
41431955 |
Appl. No.: |
16/406646 |
Filed: |
May 8, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14872371 |
Oct 1, 2015 |
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16406646 |
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12488070 |
Jun 19, 2009 |
9173704 |
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14872371 |
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61074504 |
Jun 20, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/327 20130101;
A61B 2018/00839 20130101; A61B 2018/00386 20130101; A61B 2018/00613
20130101; A61M 2025/0019 20130101; A61M 25/0043 20130101; A61B
2018/0097 20130101; A61M 2205/054 20130101; A61B 18/1492 20130101;
A61B 2018/00357 20130101 |
International
Class: |
A61M 25/00 20060101
A61M025/00; A61B 18/14 20060101 A61B018/14; A61N 1/32 20060101
A61N001/32 |
Claims
1. A method comprising: connecting a generator to a at least two
electrodes, wherein the electrodes are configured to be positioned
on an implanted medical device; and applying a predetermined set of
electrical pulses to the at least two electrodes; wherein the
predetermined set of electrical pulses are configured to
non-thermally ablate an undesirable cellular growth that may have
formed around the implanted medical device.
2. The method of claim 1, wherein the non-thermal ablation is
irreversible electroporation.
3. The method of claim 2, wherein the predetermined set of
electrical pulses comprise a voltage up to 3,000 volts and at least
10 total pulses.
4. The method of claim 1, wherein the undesirable cellular growth
may comprise a fibrin sheath, infectious cells, a biofilm, or
smooth muscle cells.
5. The method of claim 1, wherein applying a predetermined set of
electrical pulses to the at least two electrodes is configured to
prevent the removal of the implanted medical device.
6. The method of claim 1, further comprising the step of: applying
the predetermined set of electrical pulses at a predetermined
schedule.
7. The method of claim 6, wherein the predetermined set of
electrical pulses is configured to be applied by the generator
simultaneously to the at least two electrodes.
8. The method of claim 7, further comprising the step of:
alternating polarity of the at least two electrodes.
9. The method of claim 1, wherein the implanted medical device may
comprise a dialysis catheter, a port catheter, electrocardiogram
leads, a central venous catheter, or a peripherally inserted
central catheter.
10. The method of claim 1, wherein the predetermined set of
electrical pulses comprises a pulse length of less than 1
microsecond.
11. A method comprising: connecting a generator to a at least two
electrodes, wherein the electrodes are configured to be positioned
on an implanted medical device; and applying a predetermined set of
electrical pulses to the at least two electrodes; wherein the
predetermined set of electrical pulses are configured to prevent
undesirable cellular growth that may have formed around the
implanted medical device.
12. The method of claim 11, further comprising the step of:
applying the predetermined set of electrical pulses at a
predetermined schedule.
13. The method of claim 12, wherein the undesirable cellular growth
may comprise a fibrin sheath, infectious cells, a biofilm, or
smooth muscle cells.
14. The method of claim 1, wherein the predetermined set of
electrical pulses comprises a pulse length of at least 1
microsecond, a voltage up to 3,000 volts, and at least 10 total
pulses.
15. A method comprising: connecting a generator to a at least two
electrodes; advancing the electrodes through a lumen of an
implanted medical device to a target area; and applying a
predetermined set of electrical pulses to the at least two
electrodes; wherein the predetermined set of electrical pulses are
configured to non-thermally ablate an undesirable cellular growth
that may have formed near the implanted medical device at the
target area.
16. The method of claim 15, further comprising the step of:
applying the predetermined set of electrical pulses at a
predetermined schedule.
17. The method of claim 15, wherein the predetermined set of
electrical pulses comprises a pulse length of at least 1
microsecond, a voltage up to 3,000 volts, and at least 10 total
pulses.
18. The method of claim 17, wherein the undesirable cellular growth
may comprise a fibrin sheath, infectious cells, a biofilm, or
smooth muscle cells.
19. The method of claim 18, wherein the electrodes are co-axially
advanced through the lumen of the implanted medical device to the
target area.
20. The method of claim 19, wherein the non-thermal ablation is
irreversible electroporation.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. Section 119(e) to U.S. Provisional Application Ser. No.
61/074,504, filed Jun. 20, 2008, entitled "Device And Method For
The Ablation Of Fibrin Sheath Formation On A Venous Catheter Using
Electroporation", which is fully incorporated by reference
herein.
FIELD OF THE INVENTION
[0002] The present invention relates to a medical device and method
for the destruction of undesirable cellular growth on a venous
catheter, such as fibrin sheath formation and/or infectious cells,
by delivering a plurality of electrical pulses.
BACKGROUND OF THE INVENTION
[0003] Catheters, and more particularly, venous access catheters
have many very important medical applications. For example, if a
patient requires long-term dialysis therapy, a venous access
catheter, such as a chronic dialysis catheter, will be implanted in
a patient's body. Chronic dialysis catheters typically contain a
polyester cuff that is tunneled beneath the skin approximately 3-8
cm and helps to anchor the dialysis catheter to the body. The
chronic dialysis catheter is connected to a dialysis machine when
the patient is treated. Hemodialysis is a method for removing waste
products such as potassium and urea from the blood, such as in the
case of renal failure. During hemodialysis, waste products that
have accumulated in the blood because of kidney failure are
transferred via mass transfer from the blood across a semi
permeable dialysis membrane to a balanced salt solution.
[0004] In another example, a venous catheter can be used in
combination with an implanted port. A port can be implanted in
patients that require frequent access to the venous blood, such as
chemotherapy patients. An implanted port includes attachment means
for fluidly connecting a catheter. The port is implanted in a
surgically created pocket within the patient's body and has a
reservoir for delivering fluids through the catheter. One end of
the catheter is connected to the port, and the other end terminates
in a vein near the patient's heart.
[0005] Another example of a long-term venous access catheter is a
peripherally inserted central catheter, also known as a PICC line.
PICC lines are placed in patients requiring long-term access for
the purpose of blood sampling and infusion of therapeutic agents
including chemotherapeutic drugs.
[0006] Notwithstanding the importance of venous catheters, one
problem that is associated with their use is the undesired
formation of fibrin sheaths along the catheter wall. See, for
example, Savader, et al., Treatment of Hemodialysis
Catheter-associated Fibrin Sheaths by rt-PA Infusion: Critical
Analysis of 124 Procedures, J. Vasc. Interv. Radiol. 2001;
12:711-715. Fibrin sheath formation is an insidious problem that
can plague essentially all central venous catheters. It has been
reported that fibrin sheath formation occurred as early as 24 hours
after catheter placement and that this phenomenon was seen on 100%
of central venous catheters in 55 patients at the time of
autopsy.
[0007] The growth of a fibrin sheath along a catheter shaft can
prevent high flow rates, adversely affect blood sampling and
infusion of chemotherapeutic drugs, and provide an environment in
which bacteria can grow, which may result in infections. Despite
fibrin sheath build up, infused fluids may still enter the blood
circulation, but when negative pressure is applied, the fibrin
sheath can be drawn into the catheter, occluding its tip, thereby
preventing aspiration. Complete encasement of the catheter tip in a
fibrin sheath may cause persistent withdrawal occlusion. This can
lead to extravasation of fluid where fluid enters the catheter to
flow into the fibrin sheath, backtracks along the outside of the
catheter, and exits out of the venous entry point and into the
tissue. The presence of a fibrin sheath on the catheter shaft may
also result in difficulty removing the venous catheter,
particularly PICC lines, from the patient.
[0008] Often patients who need prolonged intravenous regimens have
compromised peripheral venous access and thus venous catheters are
often the only means available for the delivery of necessary
treatment. Therefore, such venous catheters should be configured to
remain in a patient so that drugs and other fluids can be
effectively delivered to the patient's vasculature and to break up
any fibrin sheath growth.
[0009] There are a number of different techniques that have been
developed to address the fibrin sheath-impaired venous access
catheter. These techniques include new catheter placement, catheter
exchange over a guide wire, percutaneous fibrin sheath stripping,
and thrombolytic therapy. For example, fibrin sheaths may be
removed by mechanical disruption or stripping with a guidewire or
loop snare, or by replacing the catheter. Mechanical disruption can
help prevent the need to replace the catheter, and thereby
eliminate disruption to the patient. However, mechanical disruption
may not be effective because the fibrin sheath may not be
completely removed and often causes damage to the catheter shaft
and vessel wall. Mechanical removal of fibrin build-up may also
increase the risk of embolism due to free floating debris within
the vessel.
[0010] Replacing the catheter is also an option, but this can cause
increased trauma to the patient, increased procedure time and
costs, increased risks of pulmonary emboli, and may require
numerous attempts before removal is successful. Thus, both
mechanical disruption and catheter replacement may adversely affect
a patient's dialysis schedule, cause patient discomfort, and loss
of the original access site. Drug therapies that address the fibrin
sheaths can also result in complications and are unreliable.
[0011] Therefore, it is desirable to provide a device and method
for the destruction of undesirable cellular growth on a venous
catheter in a safe, easy, and reliable manner without having to
remove the catheter from the patient and without damaging the vein
or catheter itself.
SUMMARY OF THE DISCLOSURE
[0012] Throughout the present teachings, any and all of the one,
two, or more features and/or components disclosed or suggested
herein, explicitly or implicitly, may be practiced and/or
implemented in any combinations of two, three, or more thereof,
whenever and wherever appropriate as understood by one of ordinary
skill in the art. The various features and/or components disclosed
herein are all illustrative for the underlying concepts, and thus
are non-limiting to their actual descriptions. Any means for
achieving substantially the same functions are considered as
foreseeable alternatives and equivalents, and are thus fully
described in writing and fully enabled. The various examples,
illustrations, and embodiments described herein are by no means, in
any degree or extent, limiting the broadest scopes of the claimed
inventions presented herein or in any future applications claiming
priority to the instant application.
[0013] Disclosed herein are devices for delivering electrical
pulses for destruction and/or removal of undesirable cellular
growth formations on a venous catheter and methods of using such.
In particular, according to the principles of the present
invention, an indwelling venous catheter capable of destroying
undesirable cellular growth is provided. The catheter includes a
shaft having at least one lumen and adapted to be placed inside a
vein for long term use. A plurality of electrodes are positioned
near the shaft and are adapted to receive from a voltage generator
a plurality of electrical pulses in an amount sufficient to cause
destruction of cells in the undesirable cellular growth that have
grown around the shaft. In one aspect of the invention, a probe is
configured to be removably insertable into the at least one lumen
and the electrodes are positioned near the distal section of the
probe.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1A is a perspective view of an electroporation venous
catheter of the current invention with a plurality of electrodes at
the distal segment of the catheter.
[0015] FIG. 1B is an enlarged cross-sectional view of an
electroporation venous catheter taken along line A-A of FIG. 1A
showing the arrangement of the electrically conducting elements
within the catheter shaft wall.
[0016] FIG. 2A is a perspective view showing an electroporation
venous catheter of the current invention with electroporation
electrodes implanted in the body of a patient.
[0017] FIG. 2B is an enlarged view of the distal portion of the
catheter of FIG. 1A exhibiting fibrin sheath formation.
[0018] FIG. 3A is a partial longitudinal plan view of the distal
segment of the electroporation venous catheter showing the
arrangement of electrodes and electrically conducting elements.
[0019] FIG. 3B is an enlarged cross-sectional view of the
electroporation venous catheter taken along line B-B of FIG. 3A
showing the attachment between an electrode and an electrically
conducting element.
[0020] FIG. 4 is a partial plan view of the distal segment of the
electroporation venous catheter of FIG. 1A showing the electrical
field pattern created when all electrodes are simultaneously
energized.
[0021] FIG. 5 is a partial longitudinal view of the distal segment
of the electroporation venous catheter showing the electrical field
pattern created when only two electrodes are energized.
[0022] FIG. 6A is a plan view of an electroporation electrode probe
representing another embodiment of the current invention.
[0023] FIG. 6B is a partial longitudinal cross-sectional view of
the distal segment of a venous catheter with the electroporation
electrode probe of FIG. 6A inserted through the catheter lumen and
positioned within a fibrin sheath formation.
[0024] FIG. 7A is an enlarged longitudinal cross-sectional view of
an electroporation electrode probe representing yet another
embodiment of the current invention.
[0025] FIG. 7B is an enlarged longitudinal cross-sectional view of
the electroporation electrode probe of FIG. 7A illustrated
electrodes in a deployed position.
[0026] FIG. 7C is a partial longitudinal cross-sectional view of
the distal segment of a venous catheter with the electroporation
electrode probe of FIG. 7A inserted through the catheter lumen with
deployed electrodes positioned around the distal segment of the
catheter.
[0027] FIG. 8 is a distal end view of the venous catheter shown in
FIG. 7C illustrating the electrical field pattern created when the
deployed electrodes are energized.
[0028] FIG. 9 is a flowchart depicting the method steps for fibrin
sheath destruction using the electroporation catheter of FIG.
1A.
[0029] FIG. 10 is a flowchart depicting the method steps for fibrin
sheath removal using the electroporation electrode probe of FIG. 6A
or 7A.
[0030] FIG. 11 is a treatment setup for a patient for
synchronization of the delivery of electroporation pulses with a
specific portion of the cardiac rhythm.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Electroporation is defined as a phenomenon that makes cell
membranes permeable by exposing them to certain electric pulses. As
a function of the electrical parameters, electroporation pulses can
have two different effects on the permeability of the cell
membrane. The permeabilization of the cell membrane can be
reversible or irreversible as a function of the electrical
parameters used. Reversible electroporation is the process by which
the cellular membranes are made temporarily permeable. The cell
membrane will reseal a certain time after the pulses cease, and the
cell will survive. Reversible electroporation is most commonly used
for the introduction of therapeutic or genetic material into the
cell. Irreversible electroporation, also creates pores in the cell
membrane but these pores do not reseal, resulting in cell
death.
[0032] Irreversible electroporation has recently been discovered as
a viable alternative for the ablation of undesired tissue. See, in
particular, PCT Application No. PCT/US04/43477, filed Dec. 21,
2004. An important advantage of irreversible electroporation, as
described in the above reference application, is that the undesired
tissue is destroyed without creating a thermal effect. When tissue
is ablated with thermal effects, not only are the cells destroyed,
but the connective structure (tissue scaffold) and the structure of
blood vessels are also destroyed, and the proteins are denatured.
This thermal mode of damage detrimentally affects the tissue, that
is, it destroys the vasculature structure and bile ducts, and
produces collateral damage.
[0033] Irreversible and reversible electroporation without thermal
effect to ablate tissue offers many advantages. One advantage is
that it does not result in thermal damage to target tissue or other
tissue surrounding the target tissue. Another advantage is that it
only ablates cells and does not damage blood vessels or other
non-cellular or non-living materials such implanted medical devices
(venous catheters for example).
[0034] Fibrin sheaths that form on venous catheters are primarily
made up of smooth muscle cells with membranes. Therefore,
destruction of the fibrin sheath by irreversible electroporation
without causing any thermal effects is a viable method of treating
fibrin growth. It is also possible to destroy the cellular
structure of fibrin sheath formations using reversible
electroporation combined with a drug. This process is known as
electroporation-mediated chemotherapy and has been used to
introduce chemotherapy drugs into a tumor at an intracellular
level. What has not been previously described is the use of
electroporation-mediated chemotherapy for the introduction of
therapeutic agents, such as cytotoxic agents, into healthy but
undesirable tissue such as the smooth muscle cells of a fibrin
sheath formation. Cytotoxic agents are transported into the
interior of the cell through the transient pore formations,
ultimately causing cell death. In this manner, the underlying
cellular structure of a fibrin sheath formation can be destroyed by
the introduction of cytotoxic agents into the smooth muscles cells
comprising the sheath.
[0035] Although the following example discusses using the present
invention and method to destroy fibrin sheath growth, persons of
ordinary skill in the art will appreciate that the present device
and method can treat any undesirable cellular growth, including
infectious cells.
[0036] FIG. 1A illustrates an indwelling electroporation venous
catheter 10 with fibrin sheath destruction capabilities. The
catheter 10 is comprised of a catheter shaft 25 that extends from a
distal end opening 28 to a bifurcate hub 49 and two extension tubes
30, 32. The extension tubes 30, 32 terminate at hub connectors 34,
35 for connection to a dialysis machine. Clamps 41, 42 serve to
close off the extension tubes 30, 32 between dialysis sessions. The
catheter shaft 25 has at least a first withdrawal lumen 16 and a
second supply lumen 18, which share a common internal septum 24, as
illustrated in FIG. 1B. First lumen 16 and second lumen 18 extend
longitudinally through substantially the entire length of the
catheter shaft 25, terminating at distal openings 26 and 28,
respectively. Side holes 31 and 33 provide supplemental access to
lumens 16 and 18, respectively. FIG. 1B depicts a cross-sectional
view of the catheter taken along lines A-A of FIG. 1A illustrating
the Double-D lumen shape. Although the cross-sectional lumen
configuration shown is a Double-D shape, it is contemplated that
lumens 16 and 18 of catheter 10 may have any suitable cross-section
lumen shape as required for the particular use of catheter 10.
[0037] Catheter 10 includes an electrical connector 500 extending
proximally from hub 49 and in the illustrated embodiment positioned
between the extension tubes 30 and 32. Catheter 10 also includes a
plurality of electrodes 150 attached to the outer surface of the
catheter shaft 25. The location of the electrodes on the catheter
may be anywhere along the shaft, but the electrodes may generally
be located near the distal section of the shaft where the fibrin
sheath formation most severely compromises the fluid flow of the
device. Furthermore, the size and shape of the electrodes can vary.
For example, the electrodes can be ring-shaped, spiral-shaped, or
can exist as segmented portions. The electrodes may also be a
series of strips placed longitudinally along the catheter shaft
surface. The electrodes may be comprised of any suitable
electrically conductive material including but not limited to
stainless steel, gold, silver and other metals.
[0038] A plurality of electrically conducting elements (e.g.,
electrical wires) 160, shown in FIG. 1B, extend longitudinally
within the wall of the catheter shaft and function to connect each
electrode 150 to a source of electrical energy in the form of a
generator (not shown) by connection through the electrical
connector 500. Each electrically conducting element 160 extends
from an electrode 150 to which it is connected to terminate in
electrical connector 500. An extension cable (not shown) is
attached to electrical connector 500 to complete an electrical
circuit between the electrodes 150 and the electrical generator
through the electrically conducting elements 160. The electrically
conducting elements 160 may be comprised of any suitable
electrically conductive material including but not limited
stainless steel, copper, gold, silver and other metals. The
catheter shaft is comprised of a non-conductive material such as
urethane, and functions as an electrical insulator insulting each
electrically conducting element 160 from the other elements 160 and
ensuring that the energy is directed to the exposed electrodes.
[0039] FIGS. 2A and 2B illustrate an indwelling electroporation
venous catheter 10 of FIG. 1A implanted in the body of a patient
400. Catheter 10 is inserted into vein 404 of a patient 400 with
the distal portion of the catheter 10 located at the junction of
the superior vena cava 408 and the right atrium of the heart 412,
where blood volume and flow rates are maximized. FIG. 2B
illustrates fibrin sheath formation 200 attached to the outer wall
25 of the distal segment of catheter 10. As illustrated, the
fibrous material occludes the distal end holes 26 and 28 and side
holes 31 and 33, thus impairing the functionality of the catheter.
Fibrin sheath formation 200 may originate anywhere along the
catheter shaft 25 where platelet aggregation begins. For example,
fibrin sheath growth 200 may originate at the distal end of the
catheter and then develop into a matrix of smooth muscle cells
which can block the distal openings 26, 28 and side holes 31 and 33
of the catheter 10.
[0040] The electrodes 150 are adapted to administer electrical
pulses as necessary in order to reversibly or irreversibly
electroporate the cell membranes of the smooth muscle cells
comprising the fibrin sheath 200 located along the outer surface of
catheter shaft 25 or inside of the catheter shaft 25 within a
treatment zone. By varying parameters of voltage, number of
electrical pulse and pulse duration, the electrical field will
either produce irreversible or reversible electroporation of the
cells within the fibrin sheath 200. The pulse generator of the
present invention can be designed to deliver a range of different
voltages, currents and duration of pulses as well as number of
pulses. Typical ranges include but are not limited to a voltage
level of between 100-3000 volts, a pulse duration of between 20-200
microseconds (more preferably 50-100 microseconds), and multiple
sets of pulses (e.g. 2-5 sets) of about 2-25 pulses per set and
between 10 and-500 total pulses. The pulse generator can administer
a current in a range of from about 2,000 V/cm to about 6,000 V/cm.
The pulse generator can provide pulses which are at a specific
known duration and with a specific amount of current. For example,
the pulse generator can be designed upon activation to provide 10
pulses for 100 microseconds each providing a current of 3,800 V/cm
+/-50% +/-25%, +/-10%, +/-5%. The electroporation treatment zone is
defined by mapping the electrical field that is created by the
electrical pulses between two electrodes.
[0041] When electrical pulses are administered within the
irreversible parameter ranges, permanent pore formation occurs in
the cellular membrane, resulting in cell death of the smooth muscle
cells of the fibrin sheath. In another aspect, by proactively
administering the electrical pulses according to a predetermined
schedule, fibrin sheath growth 200 on the catheter can be prevented
altogether. Alternatively, electrical pulses may be administered
within a reversible electroporation range. Cytotoxic drugs, such as
a chemotherapy agent, may be administered through either catheter
lumen into the volume of fibrin sheath during the electroporation
treatment. Temporary pores will form in the cellular membranes of
the smooth muscle cells comprising the fibrin sheath, allowing the
transport of the drug into the intracellular structure, resulting
in cell death.
[0042] FIG. 3A illustrates an enlarged partial plan view of the
distal segment of the electroporation venous catheter 10 with
fibrin sheath removal capabilities. A plurality of electrodes 150
are disposed on the outer surface of the distal portion of the
catheter shaft 25. The electrodes 150 are shaped as rings coaxially
surrounding the catheter shaft. In this embodiment, each electrode
150 is individually electrically coupled to an electrically
conducting element 160. As an example, the distal most electrode
150A is connected to electrically conducting element 160A, which
extends within the side wall of the catheter shaft 25 from
electrical connector 500 (FIG. 1A) to electrode 150A. Electrically
conducting element 160B extends from connector 500 and terminates
at electrode 150B. Electrode 150C, as shown, circumferentially
surrounds the outer walls of both lumens 16 and 18 and is
electrically coupled to electrically conducting element 160C which
terminates in the catheter side wall at the location of electrode
150C. Similarly, electrode 1500, 150E and 150F are electrically
coupled to conducting elements 160D, 160E and 160F
respectively.
[0043] FIG. 3B depicts an enlarged cross-sectional view of catheter
10 taken along lines B-B of FIG. 3A at the location of electrode
150D. Catheter shaft 25 is comprised of lumens 16 and 18 separated
by a septum 24. Coaxially surrounding shaft 25 is ring electrode
150D. Electrically conducting elements 160A, 160B, 160C and 160D
are also illustrated embedded within the catheter shaft 25 wall.
The catheter shaft 25 is comprised of a non-conductive urethane
material and functions as an electrical insulator insulting each
electrically conducting element from the other elements and from
those electrodes 150 not physically coupled to the conducting
element. Electrically conducting element 160D is shown in FIG. 3B
as being electrically coupled to electrode 150D by an electrically
conductive material 320. To create the coupling, the catheter shaft
25 surface may be skived until the outer surface of the coupling
wire 160D is exposed. This process creates skive pocket 310. Pocket
310 is filled with electrically conductive material 320 to create
an electrically conductive pathway between electrode 150D and
electrically conducting element 160D.
[0044] Other methods known in the art for electrically coupling the
electrodes 150 and electrically conducting elements 160 are within
the scope of this invention. Examples of coupling methods include
spot welding the electrode 150 to the conducting element 160,
soldering and mechanical crimping, among other techniques. Other
electrically conducting element configurations are also within the
scope of this invention. For manufacturing efficiencies, for
example, shaft 25 may be extruded with all electrically conducting
elements 160 embedded in the shaft for substantially the entire
length of the catheter shaft 25. Only the electrode 150 to which
the conducting element 160 is coupled will be activated when the
electrical circuit is energized. Those segments of the electrically
coupling elements 160 distal of the electrode 150 connection will
not generate an electrical field of sufficient intensity to induce
a clinical effect when activated since they are not connected to
any other electrodes.
[0045] FIG. 4 depicts the electrical field pattern created when
electrical pulses are applied to the catheter 10 shown in FIG. 3A.
In the embodiment shown, electrical pulses may be simultaneously
applied to all electrodes 150A-150F with alternating polarity. As
an example, electrode 150F may have a positive polarity, electrode
150E a negative polarity, electrode 150D a positive polarity,
electrode 150C a negative polarity, electrode 150B a positive
polarity and electrode 150A a negative polarity. This arrangement
creates the electrical field pattern illustrated by field gradient
lines 210, 220 and 230. The voltage pulse generator (not shown) is
configured to generate electrical pulses between electrodes in an
amount which is sufficient to induce irreversible electroporation
of fibrin sheath smooth muscle cells without creating a clinically
significant thermal effect to the treatment site. Specifically, the
electrical pulses will create permanent openings in the smooth
muscles cells comprising the fibrin sheath, thereby invoking cell
death without creating a clinically significant thermal effect. The
smooth muscle cells will remain in situ and are subsequently
removed by natural body processes.
[0046] The strongest (defined as volts/cm) electrical field is
nearest to the electrodes 150 and is depicted by gradient line 210
in FIG. 4. As the distance away from the electrode 150 increases,
the strength of the electrical field decreases. Gradient line 230
represents the outer perimeter of irreversible electroporation
effect and as such defines the outer boundary of cell kill zone. As
an example, any fibrin or other bio-film growth on the surface of
the catheter within the outer perimeter 230 will undergo cell death
by irreversible electroporation.
[0047] Because the voltage pulse generation pattern from the
generator does not generate damaging thermal effect, and because
the voltage pulses only ablate living cells, the treatment does not
damage blood, blood vessels or other non-cellular or non-living
materials such as the venous catheter itself.
[0048] By utilizing separate electrically conducting elements 160
for each electrode 150, different fibrin sheath growth 200 segments
may be treated independently. For example, a computer (not shown)
within the generator can control the firing of each electrode pair
independently and according to a predetermined pattern.
Alternatively, the creation of a series of electrical fields may be
accomplished by sequentially firing pairs of electrodes within one
treatment session to ensure that the entire length of the fibrin
sheath is treated. Sequentially polarizing and applying electrical
energy to a subset of the total number of electrodes as described
herein may be used to target fibrin growth on a specific segment of
the catheter shaft. As an example, FIG. 5 depicts the electrical
fields created when electrical pulses are applied to two electrodes
only. Electrode 150B may be set to have a positive polarity and
electrode 150C a negative polarity. When electrical pulses are
applied to these two electrodes, an electrical field pattern is
created as illustrated by gradient lines 210, 220 and 230. Fibrin
sheath build-up within the outer perimeter of gradient line 230
will be effectively destroyed.
[0049] In another aspect of the invention, the device and method
can be used to cause the destruction of infectious cells, such as
catheter-related bacteremia, that have grown around the indwelling
catheter. These infectious cells can be located anywhere along the
indwelling shaft. Research has also shown that infectious cells can
form in combination with fibrin sheath growths, because fibrin
sheath can enhance catheter-related bacteremia by providing an
interface for adherence and colonization. These pathogens may then
produce a "biofilm" which is impenetrable to systemic antibiotics
leading to a cause of catheter dysfunction, subsequent removal, and
the attendant increase in morbidity and mortality. Referring again
to FIG. 4, the pulse parameters that characterize the field
gradient line can be adjusted to vary the treatment zone according
to the location of the fibrin sheath growth and/or infectious cells
to be destroyed. Furthermore, in some embodiments of the invention,
the electrodes can be positioned at any location necessary to
destroy any such infectious cells that have grown around the
indwelling catheter. For example, the electrodes can be positioned
at a proximal section of the indwelling catheter for treating
infectious cells, that have grown around the tunneled portion of
the catheter. In addition, the electrodes can be positioned to
destroy infectious cells that have grown near the insertion site of
the indwelling catheter.
[0050] In another aspect of the invention, by periodically
administering the electrical pulses according to a predetermined
schedule, fibrin sheath growth on the catheter shaft 20 can be
prevented altogether. As an example, the formation of a fibrin
sheath may occur as early as 24 hours after catheter implantation.
Smooth muscle cells develop within seven days. Application of
electrical pulses applied to fibrin sheath at regular intervals
post-implantation may be effective in preventing fibrin sheath
growth during the catheter implantation period.
[0051] Referring now to FIG. 6A and 6B, FIG. 6A is a plan view of
an electroporation probe 600 representing another embodiment of the
current invention. In this embodiment an electroporation probe 600
is comprised of an electrical connector 601, a flexible shaft body
602 on which two electrodes 603 and 604 are positioned in a coaxial
arrangement with the shaft, and a distal end or tip 605. The
electrodes are preferably positioned near a distal section of the
shaft. As previously described electrically conductive elements 606
and 607 extend longitudinally from the electrical connector 601 to
the electrodes 603 and electrode 604 respectively. The electrically
conductive elements 606 and 607 may be embedded within the wall of
the shaft 602, as previously described, or alternatively may be
insulated and positioned within a lumen of shaft 602.
[0052] FIG. 6B is a partial longitudinal cross-sectional view of
the distal segment of a venous catheter 11 with the distal section
of electrode probe 600 of FIG. 6A inserted through the catheter
lumen 16 and positioned within a fibrin sheath formation 200. To
destroy the fibrin sheath 200, the electrode probe 600 is inserted
into the catheter lumen 16 and advanced through the distal end hole
26. Electrode probe distal tip 605 may be tapered to provide a
non-traumatic leading edge capable of advancing through the sheath
formation 200. Electrodes 603 and 604 are positioned within the
fibrin sheath formation 200 such that when electrical pulses are
applied, an electrical field (not shown) will be created that
encompasses the fibrin sheath 200 in its entirety. After the
electroporation process has destroyed the fibrin sheath, the probe
is removed from the catheter. Alternatively, cytotoxic agents may
be administered through lumen 16 and directed into the fibrin
formation. Electroporation pulses may be applied to reversibly
electroporate the smooth muscle cells of sheath 200, creating a
pathway through the cell membrane for the agent to enter the
cell.
[0053] The embodiment illustrated in FIGS. 6A and 6B is
particularly advantageous when treating a fibrin sheath formation
that has advanced into the lumen of the catheter and occludes the
end holes and/or side holes of the catheter. Another advantage of
the embodiment of FIG. 6A is that the probe is a separate device
inserted into the patient through the implanted catheter only when
treatment is required and then is removed immediately after
treatment. The probe is not part of the implanted catheter device
and is removed immediately after treatment. Utilizing a separate
device to perform electroporation reduces the possibility of
electrode or conducting wire damage due to long term implantation
as well as simplifying the manufacturing of the device and costs
associated with the manufacture.
[0054] FIGS. 7A-7C illustrate a third embodiment of the present
invention wherein the electroporation probe 700 is comprised of
deployable electrodes. As with the previous embodiment, the
electroporation probe 700 is inserted into the lumen of a catheter
prior to the application of electrical pulses, and is removed after
treatment. Referring first to FIG. 7A, electrode probe 700 is
comprised of an electrical connector hub 712, an outer sheath 701
extending from the hub 712 to a distal end hole 702, and a
plurality of electrically conducting elements 709 and 704 arranged
within the outer sheath 701 and within a lumen. Electrically
conducting elements 709 and 704 are connected proximally to the
electrical connector/hub 712 and extend distally within the outer
sheath 701 for substantially the entire length of the sheath.
Insulating sleeves 707 and 703 coaxially surround electrically
conducting elements 709 and 704 from the hub 712 to insulation
distal ends 721 and 723. Un-insulated portions 711 and 705 of
electrically conducting elements 709 and 704 extend distally.
Portions 711 and 705, being un-insulated, act as electrodes when
the electrical circuit is energized.
[0055] Button 713 on hub 712 is used to deploy and retract the
electrically conducting elements 709 and 704 relative to the outer
sheath 701. The undeployed position of electroporation probe 700 is
illustrated in FIG. 7A. As shown, the electrically conducting
elements 709 and 704 are completely contained within the lumen of
the outer sheath 701 including the un-insulated portions 711 and
705. The fully deployed position of the electrode probe 700 is
illustrated in FIG. 7B. Button 713 is advanced distally to deploy
the distal sections of electrically conducting element 709 and 704
out of the distal end hole 702 of outer sheath 701. When fully
deployed, the distal section of the electrically conducting
elements 709 and 704 extend outwardly from end hole 702, with a
profile that curves outwardly and then extends proximally in a
substantially parallel relationship with the longitudinal axis of
the probe 700. The distal portion of insulating sleeves 707 and 703
form at least part of the curve terminating at points 721 and 723.
The un-insulated portions 711 and 705 form the active electrodes
and extend from insulation end points 721 and 723 in a proximal
direction adjacent (such as parallel to) the outer wall of outer
sheath 701.
[0056] Electrically conductive elements 704 and 709 may be formed
of any suitable electrically conductive material including but not
limited stainless steel, gold, silver and other metals including
shape-memory materials such as nitinol. Nitinol is an alloy with
super-elastic characteristics which enables it to return to a
pre-determined expanded shape upon release from a constrained
position. The outer sheath 701 constrains the distal segments of
the undeployed electrically conductive elements 704 and 709 in a
substantially straight distal configuration. Once the electrodes
are deployed from the distal end of the outer sheath 701 as
previously described, the distal sections of electrically
conductive elements 704 and 709 form the "J-hook" curved profile
shown in FIG. 7B.
[0057] FIG. 7C illustrates a partial longitudinal cross-sectional
view of a catheter 11 with the electrode probe 700 in a deployed
position. In use, the undeployed electrode probe 700 is inserted
into lumen 18 of catheter 11 and advanced to the distal end hole
28. Once correctly positioned, button 713 (shown in FIG. 7B) is
advanced in the direction shown by the hub arrow to deploy the
distal sections of electrically conducting elements 709 and 704
outside of the outer sheath 701 and the catheter distal end hole
28. When fully deployed, the exposed segments 711 and 705 of
electrically conducting elements 709 and 704 extend in a proximal
direction adjacent to and parallel to the outer wall of catheter
shaft 25.
[0058] FIG. 8 is an enlarged end view of the catheter of FIG. 7C
depicting the electrical fields created when electrical pulses are
applied to electrode probe 700. Application of pulses creates an
electrical field pattern between the un-insulated portions 711 and
705 (shown in FIG. 7C) of the electrically conducting elements.
This arrangement creates the electrical field pattern illustrated
by field gradient lines 210, 220 and 230. The strongest (defined as
volts/cm) electrical field is nearest to the active electrodes and
is depicted by gradient line 210. As the distance away from the
electrodes increase, the strength of the electrical field
decreases. Gradient line 230 represents the outer perimeter of
irreversible electroporation effect and as such defines the outer
boundary of cell kill zone. As an example, any fibrin or other
bio-film growth on the surface of the catheter within the outer
perimeter 230 will undergo cell death by irreversible
electroporation.
[0059] If fibrin sheath has formed around end hole 26, electrode
probe 700 may be inserted into lumen 16 (shown in FIG. 7C),
positioned and then electrodes deployed as previously described.
Application of electrical pulses will create an electrical field as
shown in FIG. 8, except the field will be centered around end hole
26 rather than end hole 28. It is also within the scope of this
invention to utilize two electrode probes of opposite polarity with
one probe placed in each lumen. In this embodiment, the electrical
field may be created between the two probes, creating an electrical
field similar to that illustrated in FIG. 4.
[0060] The deploying electrode probe 700 illustrated in FIGS. 7A-C
and 8 is particularly advantageous in destroying fibrin build-up
along the outer surface of the distal segment of an implanted
catheter. Probe 700 may be used to clear fibrin sheath formations
from each lumen of a catheter as well as to irreversibly
electroporate fibrin sheath occluding side holes located near the
distal end of the catheter. The number of electrically conducting
elements 704 and 709 may be varied to accommodate various size
catheters and fibrin sheath volumes. In addition, the length of the
exposed segment 711 and 705 may be adjusted based on the catheter
length and/or the length of the fibrin formation extending
proximally from the distal end holes of the catheter. It is also
within the scope of this invention to configure a probe with two
deployable electrodes which, when deployed, are arranged at an
angle relative to each other of less than 180 degrees (i.e., not
parallel to each other). After applying electrical pulses to create
an electrical field pattern, the probe may be rotated and pulse
applied again to create a second electrical field pattern. This
process is repeated until the entire 360 degree circumference of
the outer surface of the catheter has been treated. It is also
understood that any of the embodiments illustrated may be used to
reversibly electroporate the fibrin sheath for the purpose of
introducing therapeutic agents into the smooth muscle cells.
[0061] FIG. 9 illustrates the procedural steps associated with
performing irreversible or reversible electroporation treatment
using the device which is depicted in FIGS. 1-5. After the fibrin
sheath formation has been detected and the location of the
formation determined using ultrasound or fluoroscopic imaging,
electrical connector 500 is connected to an electrical generator
(801) using an extension cable. This completes an electrical
circuit between the electrodes 150 and the generator via the
electrically conducting elements 160. Electrical pulses are applied
across the electrodes in the desired pattern to electroporate the
smooth muscle cells of the fibrin sheath (802). If the electrical
generator treatment parameters are set to deliver electrical pulses
within the reversible range (803), therapeutic agents may be
injected through the catheter lumens (804) and pass into the fibrin
sheath formation through either the side holes or end holes of the
catheter. After treatment, the extension cable is disconnected from
the electrical connector (805). Non-thermal death of the smooth
muscle cells will occur within the first twenty-four hours after
electroporation treatment followed by a cellular breakdown of the
fibrin sheath.
[0062] Referring now to FIG. 10, the method of performing
electroporation treatment using the device depicting in FIGS. 6A-B
or FIG. 7A-C is illustrated. After the fibrin sheath formation has
been detected and the location of the formation determined using
ultrasound or fluoroscopic imaging, electrode probe 600 (FIGS.
6A-B) or 700 (FIGS. 7A-C) is inserted into the venous catheter
(901). The probe is then positioned relative to the fibrin sheath
location as previously described. The electrical connector 601 or
712 is then connected to an electrical generator using an extension
cable (902). If using electrode probe 700, the electrodes are
deployed (904) and positioned outside of the catheter shaft as
shown in FIG. 7C. Electrical pulses are then applied across the
electrodes (905) creating a field gradient sufficient to
non-thermally electroporate the smooth muscle cells present in the
fibrin sheath. If the electrical generator treatment parameters are
set to deliver electrical pulses within the reversible range (906),
therapeutic agents may be injected through the catheter lumen (907)
passing into the fibrin sheath formation through either the side
holes or end holes of the catheter. Alternatively, the
electroporation probe may be configured to include a lumen through
which agents may be administered. If using probe 700, the
electrodes are then retracted (908) within the outer sheath 701.
After the procedure is complete, the probe is removed from the
catheter (909). Non-thermal death of the smooth muscle cells occur
after electroporation treatment followed by a cellular breakdown of
the fibrin sheath.
[0063] In one embodiment, the electroporation pulses can be
synchronously matched to specifically repeatable phases of the
cardiac cycle to protect cardiac cellular functioning. See, for
example, U.S. patent application Ser. No. 61/181,727, filed May 28,
2009, entitled "Algorithm For Synchronizing Energy Delivery To The
Cardiac Rhythm", which is fully incorporated by reference herein.
This feature is especially useful when the electroporation pulses
are delivered in a location that is near the heart. FIG. 11
illustrates a treatment setup for a patient for synchronization of
the delivery of electroporation pulses with a specific portion of
the cardiac rhythm. Electrocardiogram (ECG) leads 17, 19, 21 are
adapted to be attached to the patient for receiving electrical
signals which are generated by the patient's cardiac cycle. The ECG
leads transmit the ECG electrical signals to an electrocardiogram
unit 23. The electrocardiogram unit 23 can transmit this
information to a synchronization device 25 which can include
hardware or software to interpret ECG data. If the synchronization
device 25 determines that it is safe to deliver electroporation
pulses, it sends a control signal to a pulse generator 27. The
pulse generator 27 is adapted to connect to electrical connector
500 for delivering electroporation pulses. Each of the
synchronization device 25 and pulse generator 27 can be implemented
in a computer so that they can be programmed.
[0064] The present invention affords several advantages. Fibrin
sheath growths are destroyed without having to remove the catheter
from the patient. The treatment is minimally-invasive and highly
efficacious. Because irreversible electroporation does not create
thermal activity, the catheter is not damaged by the treatment.
Fibrin sheath growths are treated quickly, and the catheters can be
maintained according to a predetermined schedule to insure that the
distal openings remain clear.
[0065] Although the irreversible electroporation device and method
has been described herein for use with dual-lumen catheters, it
should be understood that the irreversible electroporation device
can be used with single lumen catheters or multiple-lumen
catheters. Another type of venous catheter which is prone to fibrin
sheath formation is a venous catheter that is connected to an
implanted port. An example of a venous catheter attached to an
implanted port is disclosed in U.S. Pat. Application Publication
No. 2007/0078391, which is incorporated herein by reference.
Electrode probe devices described in FIGS. 6A-B and 7A-C may be
used to remove fibrin sheath from catheter shafts connected to
implanted port devices. In the case of port devices, the probe may
be inserted through a needle lumen that has been inserted into the
septum. The probe device may include a guidewire lumen to assist in
tracking through the stem channel and into the catheter shaft
lumen. Fibrin sheath formations on PICC lines or other central
venous catheters may also be destroyed using the devices and
methods illustrated herein.
[0066] While the embodiments shown use pulses that cause IRE,
persons of ordinary skill in the art will appreciate that other
types of pulses can be used for the destruction of the fibrin
sheath growths. In particular, ultrashort sub-microsecond pulses
(pulses of less than 1 microsecond in duration) can be used to
induce apoptosis that cause damage to the intracellular structures
such as a cell nucleus.
[0067] The above disclosure is intended to be illustrative and not
exhaustive. This description will suggest many modifications,
variations, and alternatives may be made by ordinary skill in this
art without departing from the scope of the invention. Those
familiar with the art may recognize other equivalents to the
specific embodiments described herein. Accordingly, the scope of
the invention is not limited to the foregoing specification.
* * * * *