US20160022957A1 - Device and Method for the Ablation of Fibrin Sheath Formation on a Venous Catheter - Google Patents

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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS
• 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
• 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
• 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 assess 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.
• 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.
• 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.
• 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 of124Procedures, 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.
• 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.
• 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.
• 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 ever 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.
• 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.
• 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
• 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.
• 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 DRAWINGS
• 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.
• FIG. 1B is an enlarged cross-sectional view of an electroporation venous catheter taken along line A-A ofFIG. 1A showing the arrangement of the electrically conducting elements within the catheter shaft wall.
• 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.
• FIG. 2B is an enlarged view of the distal portion of the catheter ofFIG. 1A exhibiting fibrin sheath formation.
• 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.
• FIG. 3B is an enlarged cross-sectional view of the electroporation venous catheter taken along line8-8 ofFIG. 3A showing the attachment between an electrode and an electrically conducting element.
• FIG. 4 is a partial plan view of the distal segment of the electroporation venous catheter ofFIG. 1A showing the electrical field pattern created when all electrodes are simultaneously energized.
• 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.
• FIG. 6A is a plan view of an electroporation electrode probe representing another embodiment of the current invention.
• FIG. 6B is a partial longitudinal cross-sectional view of the distal segment of a venous catheter with the electroporation electrode probe ofFIG. 6A inserted through the catheter lumen and positioned within a fibrin sheath formation.
• FIG. 7A is an enlarged longitudinal cross-sectional view of an electroporation electrode probe representing yet another embodiment of the current invention.
• FIG. 7B is an enlarged longitudinal cross-sectional view of the electroporation electrode probe ofFIG. 7A illustrated electrodes in a deployed position.
• FIG. 7C is a partial longitudinal cross-sectional view of the distal segment of a venous catheter with the electroporation electrode probe ofFIG. 7A inserted through the catheter lumen with deployed electrodes positioned around the distal segment of the catheter.
• FIG. 8 is a distal end view of the venous catheter shown inFIG. 7C illustrating the electrical field pattern created when the deployed electrodes are energized.
• FIG. 9 is a flowchart depicting the method steps for fibrin sheath destruction using the electroporation catheter ofFIG. 1A.
• FIG. 10 is a flowchart depicting the method steps for fibrin sheath removal using the electroporation electrode probe ofFIG. 6A or7A.
• 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 DRAWINGS
• 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 reseat 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.
• 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.
• 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).
• 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.
• 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.
• FIG. 1A illustrates an indwelling electroporationvenous catheter10 with fibrin sheath destruction capabilities. Thecatheter10 is comprised of acatheter shaft25 that extends from a distal end opening28 to abifurcate hub49 and twoextension tubes30,32. Theextension tubes30,32 terminate athub connectors34,35 for connection to a dialysis machine.Clamps41,42 serve to close off theextension tubes30,32 between dialysis sessions. Thecatheter shaft25 has at least afirst withdrawal lumen16 and asecond supply lumen18, which share a commoninternal septum24, as illustrated inFIG. 1B.First lumen16 andsecond lumen18 extend longitudinally through substantially the entire length of thecatheter shaft25, terminating atdistal openings26 and28, respectively. Side holes31 and33 provide supplemental access tolumens16 and18, respectively.FIG. 1B depicts a cross-sectional view of the catheter taken along lines A-A ofFIG. 1A illustrating the Double-D lumen shape. Although the cross-sectional lumen configuration shown is a Double-D shape, it is contemplated thatlumens16 and18 ofcatheter10 may have any suitable cross-section lumen shape as required for the particular use ofcatheter10.
• Catheter10 includes anelectrical connector500 extending proximally fromhub49 and in the illustrated embodiment positioned between theextension tubes30 and32.Catheter10 also includes a plurality ofelectrodes150 attached to the outer surface of thecatheter shaft25. 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.
• A plurality of electrically conducting elements (e.g., electrical wires)160, shown inFIG. 1B, extend longitudinally within the wall of the catheter shaft and function to connect eachelectrode150 to a source of electrical energy in the form of a generator (not shown) by connection through theelectrical connector500. Each electrically conductingelement160 extends from anelectrode150 to which it is connected to terminate inelectrical connector500. An extension cable (not shown) is attached toelectrical connector500 to complete an electrical circuit between theelectrodes150 and the electrical generator through theelectrically conducting elements160. Theelectrically conducting elements160 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 conductingelement160 from theother elements160 and ensuring that the energy is directed to the exposed electrodes.
• FIGS. 2A and 2B illustrate an indwelling electroporationvenous catheter10 ofFIG. 1A implanted in the body of apatient400.Catheter10 is inserted intovein404 of apatient400 with the distal portion of thecatheter10 located at the junction of thesuperior vena cava408 and the right atrium of theheart412, where blood volume and flow rates are maximized.FIG. 2B illustratesfibrin sheath formation200 attached to theouter wall25 of the distal segment ofcatheter10. As illustrated, the fibrous material occludes the distal end holes26 and28 and side holes31 and33, thus impairing the functionality of the catheter.Fibrin sheath formation200 may originate anywhere along thecatheter shaft25 where platelet aggregation begins. For example,fibrin sheath growth200 may originate at the distal end of the catheter and then develop into a matrix of smooth muscle cells which can block thedistal openings26,28 and side holes31 and33 of thecatheter10.
• Theelectrodes150 are adapted to administer electrical pulses as necessary in order to reversibly or irreversibly electroporate the cell membranes of the smooth muscle cells comprising thefibrin sheath200 located along the outer surface ofcatheter shaft25 or inside of thecatheter shaft25 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 thefibrin sheath200. 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.
• 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 ceils of the fibrin sheath, in another aspect, by proactively administering the electrical pulses according to a predetermined schedule,fibrin sheath growth200 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.
• FIG. 3A illustrates an enlarged partial plan view of the distal segment of the electroporationvenous catheter10 with florin sheath removal capabilities. A plurality ofelectrodes150 are disposed on the outer surface of the distal portion of thecatheter shaft25. Theelectrodes150 are shaped as rings coaxially surrounding the catheter shaft. In this embodiment, eachelectrode150 is individually electrically coupled to an electrically conductingelement160. As an example, the distalmost electrode150A is connected to electrically conductingelement160A, which extends within the side wall of thecatheter shaft25 from electrical connector500 (FIG. 1A) toelectrode150A. Electrically conductingelement160B extends fromconnector500 and terminates atelectrode150B.Electrode150C, as shown, circumferentially surrounds the outer walls of bothlumens16 and18 and is electrically coupled to electrically conductingelement160C which terminates in the catheter side wall at the location ofelectrode150C. Similarly,electrode150D,150E and150F are electrically coupled to conductingelements160D,160E and160F respectively.
• FIG. 3B depicts an enlarged cross-sectional view ofcatheter10 taken along lines B-8 ofFIG. 3A at the location ofelectrode150D.Catheter shaft25 is comprised oflumens16 and18 separated by aseptum24. Coaxially surroundingshaft25 isring electrode150D. Electrically conductingelements160A,160B,160C and160D are also illustrated embedded within thecatheter shaft25 wall. Thecatheter shaft25 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 thoseelectrodes150 not physically coupled to the conducting element. Electrically conductingelement160D is shown inFIG. 3B as being electrically coupled toelectrode150D by an electricallyconductive material320. To create the coupling, thecatheter shaft25 surface may be skived until the outer surface of thecoupling wire160D is exposed. This process createsskive pocket310.Pocket310 is filled with electricallyconductive material320 to create an electrically conductive pathway betweenelectrode150D and electrically conductingelement160D.
• Other methods known in the art for electrically coupling theelectrodes150 and electrically conductingelements160 are within the scope of this invention. Examples of coupling methods include spot welding theelectrode150 to the conductingelement160, 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,shaft25 may be extruded with all electrically conductingelements160 embedded in the shaft for substantially the entire length of thecatheter shaft25. Only theelectrode150 to which the conductingelement160 is coupled will be activated when the electrical circuit is energized. Those segments of theelectrically coupling elements160 distal of theelectrode150 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.
• FIG. 4 depicts the electrical field pattern created when electrical pulses are applied to thecatheter10 shown inFIG. 3A. In the embodiment shown, electrical pulses may be simultaneously applied to allelectrodes150A-150F with alternating polarity. As an example,electrode150F may have a positive polarity,electrode150E a negative polarity,electrode150D a positive polarity,electrode150C a negative polarity,electrode150B a positive polarity andelectrode150A a negative polarity. This arrangement creates the electrical field pattern illustrated byfield gradient lines210,220 and230. 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.
• The strongest (defined as volts/cm) electrical field is nearest to theelectrodes150 and is depicted bygradient line210 inFIG. 4, As the distance away from theelectrode150 increases, the strength of the electrical field decreases.Gradient line230 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 theouter perimeter230 will undergo cell death by irreversible electroporation.
• 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.
• By utilizing separate electrically conductingelements160 for eachelectrode150, differentfibrin sheath growth200 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.Electrode150B may be set to have a positive polarity andelectrode150C a negative polarity. When electrical pulses are applied to these two electrodes, an electrical field pattern is created as illustrated bygradient lines210,220 and230. Fibrin sheath build-up within the outer perimeter ofgradient line230 will be effectively destroyed.
• 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 toFIG. 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.
• In another aspect of the invention, by periodically administering the electrical pulses according to a predetermined schedule, fibrin sheath growth on thecatheter shaft20 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.
• Referring now toFIGS. 6A and 6B,FIG. 6A is a plan view of anelectroporation probe600 representing another embodiment of the current invention. In this embodiment anelectroporation probe600 is comprised of anelectrical connector601, aflexible shaft body602 on which twoelectrodes603 and604 are positioned in a coaxial arrangement with the shaft, and a distal end ortip605. The electrodes are preferably positioned near a distal section of the shaft. As previously described electricallyconductive elements606 and607 extend longitudinally from theelectrical connector601 to theelectrodes603 andelectrode604 respectively. The electricallyconductive elements606 and607 may be embedded within the wall of theshaft602, as previously described, or alternatively may be insulated and positioned within a lumen ofshaft602.
• FIG. 6B is a partial longitudinal cross-sectional view of the distal segment of avenous catheter11 with the distal section ofelectrode probe600 ofFIG. 6A inserted through thecatheter lumen16 and positioned within afibrin sheath formation200. To destroy thefibrin sheath200, theelectrode probe600 is inserted into thecatheter lumen16 and advanced through thedistal end hole26. Electrode probedistal tip605 may be tapered to provide a non-traumatic leading edge capable of advancing through thesheath formation200.Electrodes603 and604 are positioned within thefibrin sheath formation200 such that when electrical pulses are applied, an electrical field (not shown) will be created that encompasses thefibrin sheath200 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 throughlumen16 and directed into the fibrin formation. Electroporation pulses may be applied to reversibly electroporate the smooth muscle cells ofsheath200, creating a pathway through the cell membrane for the agent to enter the cell.
• The embodiment illustrated inFIGS. 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 ofFIG. 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.
• FIGS. 7A-7C illustrate a third embodiment of the present invention wherein theelectroporation probe700 is comprised of deployable electrodes. As with the previous embodiment, theelectroporation probe700 is inserted into the lumen of a catheter prior to the application of electrical pulses, and is removed after treatment. Referring first toFIG. 7A,electrode probe700 is comprised of anelectrical connector hub712, anouter sheath701 extending from thehub712 to adistal end hole702, and a plurality of electrically conductingelements709 and704 arranged within theouter sheath701 and within a lumen. Electrically conductingelements709 and704 are connected proximally to the electrical connector/hub712 and extend distally within theouter sheath701 for substantially the entire length of the sheath. Insulatingsleeves707 and703 coaxially surround electrically conductingelements709 and704 from thehub712 to insulation distal ends721 and723.Un-insulated portions711 and705 of electrically conductingelements709 and704 extend distally.Portions711 and705, being un-insulated, act as electrodes when the electrical circuit is energized.
• Button713 onhub712 is used to deploy and retract theelectrically conducting elements709 and704 relative to theouter sheath701. The undeployed position ofelectroporation probe700 is illustrated inFIG. 7A. As shown, the electrically conductingelements709 and704 are completely contained within the lumen of theouter sheath701 including theun-insulated portions711 and705. The fully deployed position of theelectrode probe700 is illustrated inFIG. 7B.Button713 is advanced distally to deploy the distal sections of electrically conductingelement709 and704 out of thedistal end hole702 ofouter sheath701. When fully deployed, the distal section of theelectrically conducting elements709 and704 extend outwardly fromend hole702, with a profile that curves outwardly and then extends proximally in a substantially parallel relationship with the longitudinal axis of theprobe700. The distal portion of insulatingsleeves707 and703 form at least part of the curve terminating atpoints721 and723. Theun-insulated portions711 and705 form the active electrodes arid extend frominsulation end points721 and723 in a proximal direction adjacent (such as parallel to) the outer wall ofouter sheath701.
• Electricallyconductive elements704 and709 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. Theouter sheath701 constrains the distal segments of the undeployed electricallyconductive elements704 and709 in a substantially straight distal configuration. Once the electrodes are deployed from the distal end of theouter sheath701 as previously described, the distal sections of electricallyconductive elements704 and709 form the “J-hook” curved profile shown inFIG. 7B.
• FIG. 7C illustrates a partial longitudinal cross-sectional view of acatheter11 with theelectrode probe700 in a deployed position. In use, theundeployed electrode probe700 is inserted intolumen18 ofcatheter11 and advanced to thedistal end hole28. Once correctly positioned, button713 (shown inFIG. 7B) is advanced in the direction shown by the hub arrow to deploy the distal sections of electrically conductingelements709 and704 outside of theouter sheath701 and the catheterdistal end hole28. When fully deployed, the exposedsegments711 and705 of electrically conductingelements703 and704 extend in a proximal direction adjacent to and parallel to the outer wall ofcatheter shaft25.
• FIG. 8 is an enlarged end view of the catheter ofFIG. 7C depicting the electrical fields created when electrical pulses are applied toelectrode probe700. Application of pulses creates an electrical field pattern between theun-insulated portions711 and705 (shown inFIG. 7C) of the electrically conducting elements. This arrangement creates the electrical field pattern illustrated byfield gradient lines210,223 and230. The strongest (defined as volts/cm) electrical field is nearest to the active electrodes and is depicted bygradient line210. As the distance away from the electrodes increase, the strength of the electrical field decreases.Gradient line230 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 theouter perimeter230 will undergo cell death by irreversible electroporation.
• If fibrin sheath has formed aroundend hole26,electrode probe700 may be inserted into lumen16 (shown inFIG. 7C), positioned and then electrodes deployed as previously described. Application of electrical pulses will create an electrical field as shown inFIG. 8, except the field will be centered aroundend hole26 rather than endhole28. 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 inFIG. 4.
• The deployingelectrode probe700 illustrated inFIGS. 7A-C and8 is particularly advantageous in destroying fibrin build-up along the outer surface of the distal segment of an implanted catheter.Probe700 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 conductingelements704 and709 may be varied to accommodate various size catheters and fibrin sheath volumes. in addition, the length of the exposedsegment711 and705 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.
• FIG. 9 illustrates the procedural steps associated with performing irreversible or reversible electroporation treatment using the device which is depicted inFIGS. 1-5. After the fibrin sheath formation has been detected and the location of the formation determined using ultrasound or fluoroscopic imaging,electrical connector500 is connected to an electrical generator (801) using an extension cable. This completes an electrical circuit between theelectrodes150 and the generator via theelectrically conducting elements160. 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.
• Referring now toFIG. 10, the method of performing electroporation treatment using the device depicting inFIGS. 6A-B orFIG. 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 probe600 (FIGS. 6A-B) or700 (FIGS. 7A-C) is inserted into the venous catheter (901). The probe is then positioned relative to the fibrin sheath location as previously described. Theelectrical connector601 or712 is then connected to an electrical generator using an extension cable (902). If usingelectrode probe700, the electrodes are deployed (904) and positioned outside of the catheter shaft as shown inFIG. 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 usingprobe700, the electrodes are then retracted (908) within theouter sheath701. 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.
• 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 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 (EGG) leads17,19,21 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 anelectrocardiogram unit23. Theelectrocardiogram unit23 can transmit this information to asynchronization device25 which can include hardware or software to interpret ECG data. If thesynchronization device25 determines that it is safe to deliver electroporation pulses, it sends a control signal to apulse generator27. Thepulse generator27 is adapted to connect toelectrical connector500 for delivering electroporation pulses. Each of thesynchronization device25 andpulse generator27 can be implemented in a computer so that they can be programmed.
• 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.
• 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 inFIGS. 6A-B and7A-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.
• 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.
• 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.

Claims (20)

1. An indwelling venous catheter capable of destroying undesirable cellular growth comprising:

a shaft having at least one lumen and adapted to be placed inside a vein for long term use; and

a plurality of electrodes positioned near the shaft and 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 around the shaft.

2. The catheter ofclaim 1. wherein the shaft has two lumens and the electrodes are attached at a distal section of the shaft.

3. The catheter ofclaim 1, wherein the catheter is a dialysis catheter and the shaft has an arterial lumen and a venous lumen.

4. The catheter ofclaim 1, further comprising a probe adapted to be removably inserted into the shaft lumen, wherein the probe includes at least one of the electrodes.

5. The catheter ofclaim 1, further comprising:

a probe having a lumen and adapted to be removably inserted into the shaft lumen; and

at least two electrically conducting elements positioned within the probe lumen and adapted to be movable from a retracted position to a deployed position, wherein a distal section of the electrically conducting elements extend past the distal end of the shaft to define the plurality of electrodes.

6. The catheter ofclaim 5, wherein the distal section of the electrically conducting elements has a pre-curved profile that, in the deployed position, curves radially outwardly and then extends proximally along the shaft.

7. The catheter ofclaim 1, wherein at least one of the electrodes is ring-shaped and is coaxially arranged with the lumen.

8. The catheter ofclaim 1, further comprising:

a plurality of electrically conducting wires connected to the electrodes and running along the shaft.

9. The catheter ofclaim 1, wherein the electrically conducting wires are positioned within a wall of the shaft so as to electrically insulate the electrically conducting wires.

10. The catheter ofclaim 1, further comprising the voltage generator wherein the voltage generator is adapted to generate a set of between two and twenty-five electrical pulses with each pulse having a duration of from 50 to 200 microseconds and a voltage in a range of from 2,000 V/cm to 6,000 V/cm.

11. The catheter ofclaim 1, further comprising the voltage generator adapted to generate the electrical pulses in an amount sufficient to cause destruction of fibrin sheath that have grown around the shaft.

12. The catheter ofclaim 1, further comprising the voltage generator adapted to generate the electrical pulses in an amount sufficient to cause destruction of the infectious cells that have grown around the shaft.

13. The catheter ofclaim 1, further comprising a synchronization device adapted to receive electrocardiogram (ECG) signals and controls generation of the electrical pulses of the voltage generator based on the ECG signals.

14. The catheter ofclaim 1, further comprising the voltage generator adapted to generate the electrical pulses with each pulse having a duration of less than 1 microsecond.

15. An indwelling venous catheter device capable of destroying undesirable cellular growth comprising:

a shaft having at least one lumen terminating at a distal end opening, the shaft configured to be positioned inside a vein for long-term use;

a probe configured to be removably insertable into the at least one lumen;

a plurality of electrodes positioned near the probe, the electrodes being configured 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 around the shaft.

16. The catheter device ofclaim 15, wherein the probe has a tapered distal tip so as to provide a leading edge capable of advancing through the undesirable cellular growth.

17. The catheter device ofclaim 15, wherein, the probe has a lumen, further comprising:

at least two electrically conducting elements positioned within the probe lumen and adapted to be movable from a retracted position to a deployed position, wherein a distal section of the electrically conducting elements extend past the distal end opening of the shaft to define the plurality of electrodes.

18. The catheter device ofclaim 17, wherein the distal section of the electrically conducting elements has a pre-curved profile that, in the deployed position, curves radially outwardly and then extends proximally along the shaft.

19. The catheter device ofclaim 15, further comprising the voltage generator wherein the voltage generator is adapted to generate a set of between two and twenty-five electrical pulses with each pulse having a duration of from 50 to 200 microseconds and a voltage in a range of from 2,000 V/cm to 6,000 V/cm.

20. The catheter device ofclaim 15, further comprising the voltage generator adapted to generate the electrical pulses whose voltage is in a range of from 2,000 V/cm to 6,000 V/cm.

Images