Apparatus and method for reducing subcutaneous fat deposits by electroporation with improved comfort of patients

Abstract

An apparatus and method for non-invasive treatment in lieu of cosmetic surgery is disclosed. The apparatus comprises a combination of a high and low voltage pulse generators connected to two or more electrodes placed on a treatment site of the patient's body. high voltage pulses, delivered to the electrodes, create an electric field that kills subcutaneous fat cells. low voltage pulses, delivered to the same or individual electrodes provide transcutaneous electrical nerve stimulation (tens), blocking the signals of discomfort or pain that may arise from the high voltage pulsing.

Description

where:

• • d=the pulse duration;
  • b=the threshold excitation current density for an infinitely long pulse;
  • I=the threshold excitation current density for a pulse with duration d; and
  • τ=the membrane time constant for a particular excitable tissue.

For sensory nerves in the human skin, τ∇0.5 ms (millisecond) and b∇2 (mA/cm²). The strength-duration curves illustrating the Blair equation for different excitable tissues are shown in FIG. 2. The middle curve in the figure shows the strength-duration curve for the excitation of sensory nerves which are located in the skin and are responsible for the sensation of discomfort during electroporation procedure. The curves illustrate the relative increase in the threshold of excitation with the decrease in the duration of the electrical pulses for different excitable tissues. As can be seen from the middle curve, the threshold of excitation of sensory nerves (the middle curve of the three shown on the Figure) for 10-20 microsecond pulses is 20-50 times higher than that for 1 ms pulses. Electroporation is observed where the applied pulses have a duration of 10 microseconds and longer. To preserve the ability of EP pulses to kill cells but at the same time create as low of a sensation as possible in the patient, relatively shorter multiple pulses are preferred to long EP pulses. To preserve the ability to excite nerve cells in the extended area around electrodes, which is especially important when the same electrodes are used for both type of pulsing, the TENS pulses, having lower amplitudes than the EP pulses, may be selected to be significantly longer than the EP pulses, but at lower amplitudes than the EP pulses.

An excitation threshold of a nerve depends not only upon the duration of the stimulating pulse but also upon the immediate local excitation history of the nerve. FIG. 3 shows a plot of an “action potential,” which is a potential difference between the inner and the outer sides of the cell membrane as a function of time during an excitation. Normally, when a cell is at rest, the potential difference (or as commonly called, the voltage) across the membrane, called a “resting potential,” is about −90 mV. When an electric stimulus causes local depolarization of the membrane (decreases the negative potential across the membrane) to a value about −60 mV, called a “resting threshold”, the cell gets excited and an action potential starts propagating from the site of excitation along the nerve fiber. That is, as the potential difference across the membrane exceeds the resting threshold, a sudden change in the permeability of the membrane for sodium and potassium ions (Na⁺ and K⁺, respectively) occurs that causes rapid movement of these ions across the cell membrane, resulting in the action potential. The action potential propagates along the cell and depending on where it goes and where it comes from, carries different signals in the body.

As can be seen from the FIG. 3, over a period of time of about 1.5 ms the potential across the cell membrane rapidly increases from its resting threshold of about −60 mV to +40 mV and slowly returns back to the resting potential of −90 mV. There is a period of about 0.75 ms after stimulation when the nerve cannot be restimulated at all, no matter how high the stimulus is. This period is called the “absolute refractory period” (the threshold is infinitely high) and generally lasts for approximately 0.75 ms after reaching the peak of the action potential at about +40 mV. The absolutely refractory period is followed by a “relative refractory period”, where a stimulus greater than normal is needed to initiate an action potential. The evolution of the level of the excitation threshold during an action potential is shown in FIG. 3 by a dashed line.

The threshold of excitation of a cell at rest depends not only on the duration of the electrical stimulus but also on the waveform of the stimulus. The threshold for a bipolar pulse, consisting of two parts, a positive one and identical in shape but negative in polarity, is higher than that for a unipolar pulse. The reason for that is that the cell launches an acting potential only when the resting threshold of the excitation is reached. This happens when a change of the electrical charges on both sides of the membrane occurs that depolarizes it from −90 mV to −60 mV. If a bipolar pulse is applied to the cell, only the first half of the pulse causes a depolarization of the cellular membrane that can lead to a firing of an action potential. If the cell is not ready to fire after the first half of the pulse, when the current reverses and begins to flow the other direction in the second half of the pulse, the reversing electric current polarizes the membrane back to the previous level of −90 mV. In other words, all nerves including sensory are less sensitive to bipolar pulses than to unipolar of the same overall duration. Actually, their sensitivity approximately corresponds to that of a unipolar pulse with a half duration.

Bipolar rectangular pulses are known to be very efficient in cell killing by electroporation. Contrary to the sensitivity of excitable cells to electric stimulus, both directions of the electrical field, that is, positive (+) and negative (−), are equally efficient in creating pores in cellular membranes. This efficiency results because electroporation is a process is related to the difference in the energy of the porous and non-porous membrane in the presence of an electric field. This energy difference depends on the square of the amplitude (or strength) of the electric field (i.e., E²) and does not depend on the sign or polarity (+ or −) of the electric field.

From a practical stand point, however, applying balanced pulses during in-vivo electroporation treatment has one important advantage. Contrary to unipolar pulsing, that carries a direct current component into the treated tissue and creates undesired electrolytic effects on the interface of the electrodes and tissues, bipolar pulsing is free from these drawbacks. With the bipolar pulsing problems such as metal depositions from the electrodes or chemical decomposition of tissue during treatment are largely if not completely avoided.

These advantageous properties of balanced pulses, namely, lower excitability of the nerve cells, high efficiency in cell killing and freedom from electrolytic effects, make using rectangular bipolar balanced pulses a preferred mode for electroporation pulsing in the current invention. Technically, balancing of two pulses of the opposite polarities may be easily achieved by using a pulse generator having a direct current blocking capacitor electrically coupled in series to the transcutaneous electrodes.

The time diagram of the pulses applied to the electrodes are shown in FIGS. 4a and 4b. In FIGS. 4a and 4b voltage is plotted as a function of time for the In FIGS. 4a and 4b voltage is plotted as a function of time for the EP pulses designated for cell killing (the upper curve in each of FIGS. 4a and 4b), and the TENS pulses applied for mitigation of discomfort of the patient (the lower curve in each of FIGS. 4a and 4b). In FIG. 4a bipolar balanced rectangular EP pulses and exponential balanced TENS pulses are shown. This is the preferred embodiment for the EP—TENS treatment of the current invention. FIG. 4b shows unipolar exponential pulses. The time delay Δt between preselected TENS and synchronized EP is introduced into pulsing to ensure that the high voltage pulses are applied during the refractory state of the surrounding nerves to minimize discomfort of the patient. This time delay falls into a range of 0 to about 1.5 milliseconds and can be selected during the treatment procedure for the best comfort of the patient

The EP pulses depend upon the size of the electrodes and the distance between them and may be in the range of about 50 V to about 5000 V with a duration of about 10 microseconds to about 1.0 milliseconds. The TENS pulses may have duration of about 20 to about 1000 microseconds.

FIGS. 5-7 show different embodiments of applicators for combining EP and TENS treatment. In FIG. 5 two large pad electrodes, positive 50 and negative 52, provide TENS treatment for the area 54 of the skin 56 between the pads 50 and 52. One electrode of the EP generator, exemplary positive, is connected to pad 50, while the second, negative polarity electrode of the generator is connected to a needle electrode 58, thereby providing EP treatment in the area between the pad electrodes 50 and 52. In this embodiment, the pads would be applied to the skin and held there in a known manner, while the needle electode 58 would me manually or mechanically manipulated as desired in the area between the pads.

In FIG. 6 a multi-needle applicator 60 is shown having a hand piece 62. Handpiece 62 is attached to a frame 64 of a desired configuration carrying a an array of needle electrodes 66 comprising a plurality of needle electrodes 68 and 70. Some of the needle electrodes, those designated as electrodes 68, and which are primarily on the periphery of the array, may be connected to a TENS generator to function as TENS electrodes alone, while needle electrodes 70 may be connected to both the TENS and EP generators to function as both EP and TENS electrodes. It will be observed that placing the combined EP and TENS electrodes 70 inside the periphery of the TENS only electrodes 68 that a TENS coverage area exceeding the EP coverage area is achieved. The appropriate connectors 72 and 74 are used to connect the applicator 60, and thus the needle electrodes 68 and 70, to the EP and TENS generators.

FIG. 7 shows a two electrode applicator 80 including a handle 82. In this embodiment of the present invention, both electrodes 84 and 86 are common for EP and TENS processes. For this embodiment of the applicator the TENS pulses should be selected to be generally longer in duration and higher in the amplitude while the EP pulses should be short and multiple with a relatively long delay time. This choice of operating parameters of the system will ensure that the TENS treatment is provided to the whole area where the EP pulses can possibly excite the sensory nerves.

In operation, apparatus in accord with the present invention will include using TENS electrodes to create an anesthetic effect in at least the treatment volume and preferentially in a larger volume of patient tissue that includes the treatment volume. This anesthetic effect can be created by application of TENS pulses to the patient. Preferably subsequently to the creation of the anesthetic effect, EP pulses can be applied to the treatment, resulting in the death of some or all of the subcutaneous fat cells in the treatment volume. Other patient tissue treatment volumes can then be treated similarly. In this manner then, the present invention provides apparatus and method for reducing subcutaneous fat deposits by electroporation with improved comfort of patients.

The present invention has been described in language more or less specific as to the apparatus and method features. It is to be understood, however, that the present invention is not limited to the specific features described, since the apparatus and method herein disclosed comprise exemplary forms of putting the present invention into effect. The invention is, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims appropriately interpreted in accordance with the doctrine of equivalency and other applicable judicial doctrines.

Claims

1. An apparatus for reducing subcutaneous fat deposits by electroporation with improved comfort of patients comprising:

an applicator comprising two sets of electrodes, the first and the second, said first set of electrodes are high voltage electrodes adapted for engaging the skin of a patient and applying a high amplitude pulsed electric field to the area of skin and the subcutaneous volume of tissues to be treated by electroporation, said second set of electrodes adapted for transcutaneous electrical nerve stimulation of the skin and the volume of the subcutaneous tissue over an area generally larger than the area of electroporation treatment;

a generator of high voltage pulses for applying pulsed electric field to the first set of electrodes, said pulses generating an electric field above the upper electroporation limit for subcutaneous fat cells in the volume of the subcutaneous tissue to be treated;

a generator for generating low voltage pulses for applying pulsed electric field to the second set of electrodes, said amplitude of the electric field is adapted for Transcutaneous Electrical Nerve Stimulation (tens) of the skin and subcutaneous tissue;

a synchronizing circuit connected to said high and said low voltage pulse generators and providing triggering of the high voltage pulses with a controllable delay after the tens pulses, and

connectors connecting said generators of high and low voltage electrical pulses with corresponding high and low voltage electrodes.

2. An apparatus according to claim 1 wherein the two sets of electrodes in the applicator share at least some electrodes to which both the high voltage pulses for electroporation and low voltage pulses for tens are applied.

3. An apparatus according to claim 1 wherein said high voltage pulses have duration in a range of 10 microseconds to 1 millisecond.

4. An apparatus according to claim 1 wherein the amplitude of the electric field applied to the treated volume falls in a range of 20 Volt/mm to 2000 Volt/mm.

5. An apparatus according to claim 1 wherein said delay of the high voltage pulses relatively to the tens pulses falls into the time range of 0 to 1.5 milliseconds.

6. An apparatus according to claim 1 wherein both low and high voltage pulses are electrically balanced in such a manner that in average no direct current is passing through the treatment volume.

7. An apparatus according to claim 1 wherein high voltage pulses are rectangular balanced.

8. An apparatus according to claim 1 wherein said low voltage pulses have duration in a range of 10 to 200 microseconds.

9. An apparatus according to claim 1 wherein said low voltage pulses have repetition rate in a range of 4 to 120 Hertz.

10. An apparatus according to claim 1 wherein said low voltage pulses have amplitude in the range from 10 to 100 V.

11. A method for reducing subcutaneous fat deposits by electroporation with improved comfort of patients comprising:

providing an applicator comprising first and second sets of electrodes, wherein first set of electrodes are high voltage electrodes are configured for engaging the skin of a patient and applying a high amplitude pulsed electric field to the area of skin and the subcutaneous volume of tissues to be treated by electroporation and wherein said second set of electrodes are configured for transcutaneous electrical nerve stimulation of the skin and the volume of the subcutaneous tissue over an area generally larger than the area of electroporation treatment;

providing a generator of high voltage pulses for applying pulsed electric field to the first set of electrodes, said pulses generating an electric field above the upper electroporation limit for subcutaneous fat cells in the volume of the subcutaneous tissue to be treated;

providing a generator for generating low voltage pulses for applying pulsed electric field to the second set of electrodes, said amplitude of the electric field providing transcutaneous electrical nerve stimulation (tens) of the skin and subcutaneous tissue;

providing a synchronizing circuit connected to said high and said low voltage pulse generators and providing triggering of the high voltage pulses with a controllable delay after the tens pulses;

connecting said generators of high and low voltage electrical pulses with corresponding high and low voltage electrodes; and

applying tens pulses via said second set of electrodes to the area in and around of the area to be treated and high voltage pulses via said first set of electrodes with an amplitude sufficient to cause death to subcutaneous fat cells.

12. An apparatus for reducing subcutaneous fat deposits in a predetermined treatment volume beneath a predetermined area of a patient's skin by electroporation with improved comfort for the patient, said apparatus comprises:

first and second electrode sets, wherein said first electrode set comprises:

at least a pair of electroporation electrodes, said electroporation electrodes being provided for applying a pulsed electric field to the predetermined area of skin and the subcutaneous volume of tissues; and

wherein said second electrode set comprises:

at least a pair of tens electrodes, said tens electrodes being configured for transcutaneous electrical stimulation of the patient over a tissue volume including at least the predetermined treatment volume;

a generator of high voltage pulses for applying a pulsed electric field to the predetermined area via said first electrode set, said pulses generating an electric field above the upper electroporation limit for subcutaneous fat cells in the volume of the subcutaneous tissue to be treated;

a generator for generating low voltage pulses for applying a pulsed electric field to the predetermined area via said second electrode set, wherein the amplitude of the low voltage electric field is chosen to provide transcutaneous electrical nerve stimulation (tens) of the nerves of the skin and subcutaneous tissue in an area larger than the predetermined area;

a synchronizing circuit connected to said high and said low voltage pulse generators and providing triggering of the high voltage pulses with a controllable delay after the tens pulses, and

connectors connecting said generators of high and low voltage electrical pulses with corresponding electroporation and tens electrodes.

13. An apparatus according to claim 12 wherein the two sets of electrodes in the applicator share at least some electrodes to which both the high voltage pulses for electroporation and low voltage pulses for tens are applied.

14. An apparatus according to claim 12 wherein said delay of the high voltage pulses relatively to the tens pulses falls into the time range of 0 to 1.5 milliseconds.

15. An apparatus according to claim 12 wherein both low and high voltage pulses are electrically balanced in such a manner that in average no direct current is passing through the treatment volume.

16. An apparatus according to claim 12 wherein high voltage pulses are rectangular balanced.

17. A method for reducing subcutaneous fat deposits in a treatment volume by electroporation with improved patient comfort, said method comprising:

applying a plurality of electroporation electric field pulses to the treatment volume to induce subcutaneous fat cell death by electroporation; and

applying a plurality of tens electric field pulses at least to the treatment volume to improve patient comfort by transcutaneous electric nerve stimulation at least in the treatment volume.

18. The method of claim 17 wherein the tens electric field is applied to at least the treatment volume prior to application of the electroporation field.

19. The method of claim 17 wherein the applied electroporation and tens pulses are synchronized such that a tens pulse is applied to at least to the treatment volume prior to application of an electroporation pulse.

20. The method of claim 19 wherein application of an electroporation pulse relative to the application of a tens pulse is delayed by a time in the range of about 0 to about 1.5 milliseconds.

21. The method of claim 17 wherein both electroporation and tens pulses are electrically balanced in such a manner that in average no direct current is passing through the treatment volume.

22. The method of claim 1 wherein the electroporation pulses are rectangularly balanced.