HK40085051A - Pulsed electric field waveform manipulation and use - Google Patents

Description

Pulsed electric field waveform operation and use

Cross Reference to Related Applications

This application claims priority AND benefit from U.S. provisional patent application No. 63/007,233 entitled "PULSED ELECTRIC FIELD WAVEFORM MANIPULATION AND USE" filed on 8/4/2020 AND U.S. provisional patent application No. 63/078,784 entitled "PULSED ELECTRIC FIELD WAVEFORM MANIPULATION AND USE" filed on 15/9/2020. The disclosure of the aforementioned application is incorporated by reference herein in its entirety for all purposes.

Background

Various devices and methods have been developed for delivering therapeutic energy to the body to treat diseases and afflictions. In some cases, such delivery is to tissue within a body lumen, channel, or similar anatomical structure, in order to treat diseased tissue along or within the channel wall, or in order to affect a disease associated with or accessible through the channel. Such devices typically include a flexible elongate shaft for traversing tortuous luminal anatomy, and an energy delivery element mounted on the shaft to deliver such energy to a remote or closed location, such as a body lumen. Such devices have been developed for treating blood vessels such as the passageways of the lungs or the vasculature.

Various different types of energy have been used for therapeutic treatment, including radiofrequency energy, microwave energy, high Intensity Focused Ultrasound (HIFU) energy, and Pulsed Electric Field (PEF) energy, to name a few. PEF energy typically provides a high energy discharge in a very short period of time. Thus, low voltage energy from the dc power source is converted into a high intensity pulsed electric field. High intensity energy is stored in capacitors that are released to the target tissue at different electrical intensities (20-80 kV cm "1) and times (< 1 s).

PEF energy is delivered in a non-thermal manner (i.e., below the threshold for cell death due to thermal injury). Thus, when extracellular matrix is present, it is retained, while the target tissue retains its structural architecture including blood and lymphatic vessels. Thus, sensitive structures such as biological lumens, blood vessels, nerves, etc. can be preserved, which is critical for maintaining the integrity and functionality of the tissue. This provides a number of benefits. First, this allows for the treatment of tissues that are generally considered untreatable by conventional methods. Because tissue cannot be surgically separated from sensitive structures sufficiently efficiently, target tissue in the vicinity of sensitive structures cannot generally be surgically excised. Also, many conventional non-surgical therapies are contraindicated because the therapy may cause damage to sensitive structures or because the therapy is considered ineffective due to proximity to sensitive structures. Furthermore, the ability to treat tissue near sensitive structures also provides a more comprehensive treatment, as malignant edges are not left near sensitive structures. The persistence of the structural architecture also allows for the natural influx of biological elements (such as components of the immune system) once the tissue is treated, or for the introduction of various agents for further therapeutic treatment.

However, the use of PEF energy involves various risks. Some of these risks are described below.

Bubble formation

In general, delivery of PEF in ionic solutions (saline, blood, interstitial fluid, etc.) occurs with electrolytic reactions that affect the compounds in solution, most notably the separation of water molecules, thereby producing hydrogen (at the active cathode) and chlorine (at the active anode) components. Therefore, these gases are considered to be electrochemically generated gases. Changing the polarity of the PEF during energy delivery will reduce the extent of blister formation by changing the item being produced. However, this term alone does not completely eliminate gas generation, as the active period of each phase of the polarity will continue to contribute to gas formation.

Bubble formation has a range of implications in clinical cases, which will vary with the location and application targeted. In tissue destruction applications, one or more electrodes are placed at the target area of the tissue to deliver PEF while communicating between the electrodes or with a remote external dispersion pad, gas formation has been clearly observed ultrasonically. It is generally considered to be an insignificant side effect of therapy delivery and is not considered to be a confounding factor that alters therapy delivery. However, gas formation helps to produce several effects, which may or may not be desirable depending on the application. In one consideration, gas formation exerts pressure on adjacent tissue regions and may distort tissue geometry, disrupt tissue architecture or displace other material within the tissue. In another consideration, gas formation may enter the blood stream prior to dissolution. In turn, the circulating gaseous "bubble" may travel through the arterial access or subsequent vein, causing an embolism in downstream tissue, leading to ischemia, causing downstream cell and tissue death, pain, and other risks to the patient. The bleb may also return through systemic circulation before dissolving and cause pulmonary embolism, which may cause pain, complications, or patient death.

In addition to gases formed by inducing electrochemical reactions, gases may also be formed by vaporization. The current will increase the temperature of the ionic solution by joule heating. In case the induced temperature exceeds the phase change value, vaporization of the water content will occur. Both the vaporized and electrochemically generated gases exhibit conductivities that are orders of magnitude lower than ionic solutions. Thus, in tissue regions treated by high voltage, high energy electrical pulses, the electric field generated inside the gas may be higher than the electrical breakdown exhibited as a spark arc, or a larger combustion event depending on the size, number, type and distribution of the gaseous bubbles generated. This is a particular risk when the PEF protocol and tissue type results in the generation of large amounts of gas that are not easily removed from the local tissue environment. Such spark generation, promotion, and potential combustion events resulting from gaseous bubble formation may result in high current events affecting the performance of (or destroying) the generator, as well as distortion of the energy deposition pattern affecting the treatment outcome, creating risks including tissue burns, tissue over-treatment, tissue under-treatment, or a combination of these effects. These effects can all seriously affect the efficacy, morbidity, and potential mortality of PEF therapy.

In another consideration for gas formation, the gas: liquid: the presence of the tissue mixture will result in a heterogeneous change in the conductivity environment (essentially, current can flow preferentially around or through the gas, thereby changing its flow through the target tissue). This may result in higher energy concentrations in some areas, while absent or reduced energy concentrations in other areas. This can inherently distort energy delivery and deposition, potentially affecting the therapeutic efficacy, morbidity, and mortality of the surgery.

In addition to gas forming effects in solid tissue regions, risks also exist and may compound when delivering PEF therapy into fluid targets such as blood within the vasculature or cardiopulmonary system. Of particular concern is the rapid expulsion of air bubbles generated in the left atrium and ventricle of the heart by the heart into the aorta. These bubbles may enter the coronary circulation, carotid arteries, or other vessels. If the bubbles do not dissolve back into the fluid, they may lodge in the stenotic portion of the artery, thereby restricting or eliminating blood flow through these vessels, resulting in ischemia of downstream tissues. Blister formation has been found as a risk in cardiac therapy for indications such as atrial fibrillation through various energy modes including cryoablation, radiofrequency ablation and PEF therapy. The risk of symptomatic and asymptomatic cerebral ischemic events is significant. In addition, the tendency of the bubbles to float or move upward is such that they may enter the coronary arteries of the patient when the patient is in a supine position. In view of the likelihood and severity of problems that may be induced by gas formation during conventional procedures (such as atrial fibrillation electrical isolation procedures), clinicians and researchers have particular attention to quantifying and reducing the risk of these events in patients, including efforts to reduce or capture bleb formation. However, gas formation from PEF treatment remains a standard side effect and patient risk.

Discharge of electricity

When delivering PEF between electrodes, the high voltages typically employed can cause breakdown of the delivery device, tissue entity components, or fluids in the tissue. This may cause a discharge from the energized region of the electrode to the medium. Discharges may occur on a microscopic scale where they are not visible, or they may occur on a visible scale, often appearing as a visible "arc" or spark. The discharge is typically accompanied by a pressure wave and an audible sound that increases as the intensity of the discharge increases.

The discharge from the electrodes causes a distortion in the number and distribution of items affected by the PEF treatment. The discharge can concentrate the current to a focused area, causing a stronger therapeutic effect (overtreatment) or burning due to joule heating in the area near the discharge. This may also reduce the current in the rest of the tissue and the subsequent induced electric field (under treatment). Electrical breakdown of the current path may also cause current spikes to flow through the system, which may increase the total current that the PEF generator must generate. Such spikes may exceed the PEF generation capability of the generator or may cause high currents within the generator that may damage the internal circuitry of the generator. In addition, electrical discharges on ionic media generate reactive species (primarily nitrogen and oxygen) that will alter the composition of the media, having a significant impact on the pH of the solution and normal biomolecular interactions.

Electrical discharges may typically occur in PEF therapy due to the voltages used in these therapies. Because the cathode and anode are in close proximity to each other, the bipolar electrode arrangement is particularly susceptible to significant arcing events that may generate a discharge, also referred to as a full discharge, between the electrodes. This will cause a dead short if the voltage to distance ratio is not properly adjusted. Allowing for electrical discharge adds a degree of unpredictability and risk to the procedure. Avoiding them may reduce the efficacy of the therapy by reducing the intensity of the therapy that can be delivered.

Cavity formation

Due to the discharge, whether visible or invisible, a pressure wave is generated, i.e. an audible "pop" sound is evident. This sound is frequently encountered in many PEF therapies and is accepted as an adjunct to therapy delivery. However, when the electrical discharge and the pressure wave have sufficient intensity and repeat a sufficient number of times, the energy transferred from the pressure wave and deposited into the tissue can severely damage the tissue architecture and cells. The resulting effect is the cumulative creation of defects or cavities within the tissue at the regions near the electrodes where the strongest intensity of these effects are experienced.

The creation of a cavity adds considerable risk to the surgical delivery in or near the solid tissue and catheter system. The resulting "tearing" and destruction of tissue may damage sensitive structures such as blood vessels, nerves or other conduit systems such as bile ducts, urethra, ureter or lymphatic vessels. These shredding effects may lead to bleeding, thrombosis or embolism formation, or disruption of tissue function. Generally, PEF treatments are used in place of other therapies because they are able to retain these sensitive structures. The cavity created during treatment can compromise this benefit of most PEF therapies for tissue regions that are very close (0.1-5 mm) to the electrode.

In other cases, cavity formation and destruction via the generated pressure waves may be desirable. For example, destruction or detachment of gallstones or kidney stones may be the purpose of such effects. In addition, the fluid-filled cavities created by these effects are generally more conductive than pre-existing tissue. Thus, continued delivery of PEF (or other energy-based modality) into this generated tissue cavity will serve to augment the applicable effect of the electrode, thereby acting as a "virtual electrode". In addition, the conductive fluid will have a more uniform conductivity and provide a more evenly distributed conduit for current flow, thereby reducing the likelihood of electrical discharges into tissue that may occur when the conductivity is not uniform. Therefore, it is sometimes desirable to control cavity formation by PEF therapy.

Contraction of muscles

PEF therapy can induce its desired clinical effect by altering the target tissue, however, this may also lead to the generation of action potentials in nerves, particularly motor neurons, as well as skeletal muscle cells. The generation of action potentials in motor neurons can lead to the generation of muscle contractions during energy delivery. Muscle contraction and generation of nerve action potentials may be uncomfortable or painful if performed in conscious or semi-conscious patients. Furthermore, the electrodes delivering the treatment may move or shift, thereby risking changing the location of the treatment effect. Moving the electrodes may also puncture or damage sensitive tissue near the electrode location at the beginning of the treatment. These factors exacerbate patient and user safety issues when delivering PEF therapy. Generally, the contraction is more severe when the waveform of a given polarity is longer, with dc being the most severe and purely symmetric bi-phasic for a given pulse length, and with strong correlation for an asymmetric waveform across the entire spectrum, as the asymmetric waveform moves from purely symmetric to purely dc (from weak to strong).

In other cases, inducing muscle contraction may be a desirable secondary (or primary) effect of PEF therapy. For example, it can be used for the re-excitation of tissues that have been atrophied due to injury or clinical surgery to temporarily break nerve fibers. In one such example, PEF may be delivered near the proximal or peripheral side of the motor neuron, evoke an action potential that excites downstream skeletal muscle, maintains compactness and prevents atrophy, and promotes regeneration and recovery of muscle and neural tissue. Thus, there is sometimes a need to control and encourage muscle contraction resulting from PEF therapy.

Temperature rise

Depending on the length of time the energy is applied, as well as other factors, the delivery of energy to the tissue results in joule heating. When energy packets or pulses are delivered continuously, the energy of the individual portions is deposited simultaneously, resulting in a gradual temperature increase. This results in PEF therapy with very high to extremely high and rapid temperature rises, especially at the tissue-electrode interface and within a few millimeters of the electrode front. Without proper mitigation measures, the cumulative temperature rise may result in a range of thermal effects that may damage extracellular matrix architectural proteins (e.g., collagen), resulting in disruption of tissue function and potential danger to the patient.

Accordingly, improved therapies are needed to control these aspects of PEF and mitigate any associated risks. Such improvements should be safe, reliable, effective, easy to implement, and cost effective. The present invention will meet at least some of these objectives.

Disclosure of Invention

Described herein are embodiments of devices, systems, and methods for treating target tissue. Also, the present invention relates to the following numbered clauses:

1. a system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated from a waveform comprising one or more pulse packets for providing the therapy and comprising one or more delay periods to operate or reduce or avoid one or more secondary effects.

2. The system of claim 1, wherein the one or more secondary effects comprise bubble formation.

3. The system of claim 2, wherein the bubble formation comprises formation of bubbles having a diameter greater than or equal to 0.1 mm.

4. The system of any of the above claims, wherein each of the pulses in the one or more pulse packets has a conduction time in a range of 0.5 to 20 microseconds.

5. The system of any of claims 1-3, wherein each of the pulses in the one or more pulse packets has a continuous on-time of up to 5 microseconds.

6. The system of any of the above claims, wherein each duty cycle of the pulses is less than or equal to 2.5%.

7. The system of any of the above claims, wherein the delay period is greater than or equal to 1 microsecond.

8. The system of claim 7, wherein the delay period is in the range of 1 to 250 microseconds.

9. The system of claim 7, wherein the delay period is in the range of 10-100 microseconds.

10. The system of claim 7, wherein the delay period is greater than or equal to 100 microseconds.

11. The system of claim 7, wherein the delay period is greater than or equal to 250 microseconds.

12. The system of claim 7, wherein the delay period is greater than or equal to 500 microseconds.

13. The system of claim 7, wherein the delay period is greater than or equal to 1000 microseconds.

14. The system of claim 7, wherein the at least one electrode is configured to be positioned within an ionic solution proximate the tissue, and wherein the delay period is in a range of 100 microseconds to 10 milliseconds.

15. The system of claim 14, wherein the delay period is in a range of 250 microseconds to 1000 microseconds.

16. The system of claim 7, wherein the at least one electrode is configured to be positioned within the tissue, and wherein the delay period is in a range of 10 microseconds to 1 millisecond.

17. The system of claim 16, wherein the delay period is in a range of 25 microseconds to 100 microseconds.

18. The system of any of the above claims, wherein the one or more pulse packets comprise 100 packets, wherein each packet comprises 40 biphasic pulses.

19. The system of claim 1, wherein the one or more secondary effects comprise a discharge event.

20. The system of claim 19, wherein the discharge event comprises an arc from at least one of the at least one electrode.

21. The system of any of claims 19-20, wherein each of the pulses in the one or more pulse packets has a conduction time in a range of 1 to 50 microseconds.

22. The system of any of claims 18-20, wherein each of the pulses in the one or more pulse packets has a continuous on-time in a range of up to 20 microseconds.

23. The system of any of claims 18-22, wherein a duty cycle of each of the at least one pulse packet is less than or equal to 20%.

24. The system of claim 20, wherein the electrical discharge event comprises generation of a pressure wave against the tissue.

25. The system of claim 24, wherein the pressure waves are sufficient to create a cavity within tissue.

26. The system of claim 25, wherein a duty cycle of each of the at least one pulse packet is less than or equal to 50%.

27. The system of any of claims 25-26, wherein each of the pulses in the one or more pulse packets has a conduction time in a range of 10 to 100 microseconds.

28. The system of any of claims 25-26, wherein each of the pulses in the one or more pulse packets has a continuous on-time of up to 50 microseconds.

29. The system of any of claims 18-28, wherein the delay period is greater than or equal to 1 microsecond.

30. The system of claim 29, wherein the delay period is in the range of 1 to 500 microseconds.

31. The system of claim 29, wherein the delay period is in the range of 10-250 microseconds.

32. The system of claim 29, wherein the delay period is greater than or equal to 50 microseconds.

33. The system of claim 29, wherein the delay period is greater than or equal to 250 microseconds.

34. The system of claim 29, wherein the delay period is greater than or equal to 500 microseconds.

35. The system of claim 29, wherein the delay period is greater than or equal to 1000 microseconds.

36. The system of any of claims 18-29, wherein the at least one electrode is configured to be positioned within an ionic solution proximate the tissue, and wherein the delay period is in a range of 50 microseconds to 10 milliseconds.

37. The system of claim 36, wherein the delay period is in a range of 250 to 1000 microseconds.

38. The system according to any of claims 18-29, wherein the at least one electrode is configured to be positioned within the tissue, and wherein the delay period is in a range of 100 microseconds to 10 milliseconds.

39. The system of claim 38, wherein the delay period is in the range of 250 to 2000 microseconds.

40. The system according to any one of claims 18-29, wherein said at least one electrode is configured to be positioned within a lumen, wherein said tissue resides within a wall of said lumen, and wherein said delay period is in a range of 10 microseconds to 10 milliseconds.

41. The system of claim 40, wherein the delay period is in the range of 50 to 500 microseconds.

42. The system of any one of claims 18-41, wherein the one or more packets of pulses comprise 100 packets, wherein each packet comprises 40 biphasic pulses.

43. The system of claim 1, wherein the one or more secondary effects comprise contraction of a muscle.

44. The system of claim 43, wherein the at least one electrode is configured to create a lesion having a width, and wherein reducing or avoiding contraction of the muscle causes the at least one electrode to maintain a position in which it moves no more than 25% of the width.

45. The system of claim 44, wherein the tissue comprises cardiac tissue and the lesion comprises a focal lesion.

46. The system of any of claims 43-45, wherein the delay period is greater than or equal to 5 milliseconds.

47. The system of claim 46, wherein the delay period is greater than or equal to 10 milliseconds.

48. The system of claim 46, wherein the delay period is in a range of 5 milliseconds to 1 second.

49. The system of claim 46, wherein the delay period is in the range of 5 to 100 milliseconds.

50. The system of claim 46, wherein the delay period is in the range of 5 to 10 milliseconds.

51. The system of claim 46, wherein the delay period is in the range of 10-30 milliseconds.

52. The system of claim 46, wherein the delay period is greater than or equal to 1000 microseconds.

53. The system of any of claims 43-52, wherein the one or more pulse packets comprise 100 packets, wherein each packet comprises 40 biphasic pulses.

54. The system of any one of claims 43-53, wherein the one or more pulse packets comprise at least two packets separated by a packet delay period of at least 30 milliseconds.

55. The system of claim 54, wherein each of the packets is separated by a packet delay period of at least 30 milliseconds.

56. The system of any of the above claims, wherein the pulse comprises a biphasic pulse and the delay period comprises an interphase delay between positive and negative phases of the biphasic pulse.

57. The system of claim 56, wherein each biphasic pulse comprises an inter-phase delay.

58. The system of any of the above claims, wherein the delay period comprises an inter-packet delay.

59. The system of claim 58, wherein the inter-packet delay is in the range of 30-5000 milliseconds.

60. The system of claim 59, wherein said inter-packet delay is 30-40 milliseconds.

61. The system according to claim 59, wherein said inter-packet delay is 3000-5000 milliseconds.

62. The system of any of the above claims, wherein the delay period comprises an inter-pulse delay.

63. The system of any of the above claims, wherein the waveform comprises one or more beams, wherein each beam comprises two or more packets.

64. The system of claim 63, wherein each bundle comprises three packets, and wherein each bundle is spaced apart to facilitate delivery within the ST interval of the patient's heart rhythm.

65. The system of claim 63, wherein the delay period comprises an inter-beam delay.

66. The system of any of the above claims, wherein the waveform has a voltage amplitude of 500 to 4,000 volts.

67. The system of any of the above claims, wherein the waveform has a frequency of 300-800 kHz.

68. The system of any of the above claims, wherein each of the one or more packets has 10-200 biphasic pulses.

69. The system of any of the above claims, wherein each of the one or more packets has 20-50 biphasic pulses.

70. The system of any of the above claims, wherein the treatment comprises 5 to 100 packets.

71. The system of any of the above claims, wherein the treatment comprises 10 to 60 packets.

72. The system of any of the above claims, further comprising a remotely located dispersive electrode positionable to deliver the energy in a monopolar fashion.

73. A system for treating a tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated from a waveform comprising one or more pulse packets for providing the therapy and comprising one or more delay periods that avoid a peak temperature in the tissue that would be reached by delivery of the energy without the one or more delay periods.

74. The system of claim 73, wherein the peak temperature causes bubble formation.

75. The system of any one of claims 73-74, wherein the peak temperature is 100 degrees Celsius.

76. The system of any one of claims 73-75, wherein the peak temperature causes a discharge.

77. The system of any of claims 73-76, wherein the delay period is greater than or equal to 5 milliseconds.

78. The system of claim 77, wherein the delay period is greater than or equal to 10 milliseconds.

79. The system of claim 77, wherein the delay period is in a range of 5 milliseconds to 1 second.

80. The system of claim 77, wherein the delay period is in the range of 5 milliseconds to 100 milliseconds.

81. The system of claim 77, wherein the delay period is in the range of 5 milliseconds to 10 milliseconds.

82. The system of claim 77, wherein the delay period is in the range of 10-30 milliseconds.

83. The system of any of claims 73-82, wherein the waveform comprises one or more beams, wherein each beam comprises two or more packets.

84. The system of claim 83, wherein each bundle comprises three packets, and wherein each bundle is spaced apart to facilitate delivery within an ST interval of the patient's heart rhythm.

85. The system of any one of claims 73-84, wherein the one or more pulse packets comprise 100 packets, wherein each packet comprises 40 biphasic pulses.

86. The system of any of claims 73-85, wherein the pulse comprises a biphasic pulse and the delay period comprises an interphase delay between positive and negative phases of the biphasic pulse.

87. The system of claim 86, wherein each biphasic pulse includes the inter-phase delay.

88. The system of any one of claims 73-85, wherein the delay period comprises an inter-packet delay.

89. The system of claim 88, wherein the inter-packet delay is in the range of 30-5000 milliseconds.

90. The system of claim 88, wherein the inter-packet delay is in the range of 30-40 milliseconds.

91. The system of claim 88, wherein the inter-packet delay is in the range of 3000-5000 milliseconds.

92. The system of any one of claims 73-85, wherein the delay period comprises an inter-pulse delay.

93. The system of any of claims 73-92, wherein the waveform comprises one or more beams, wherein each beam comprises two or more packets.

94. The system of claim 93, wherein each bundle comprises three packets, and wherein each bundle is spaced to facilitate delivery within the ST interval of the patient's heart rhythm.

95. The system of claim 93, wherein the delay period comprises an inter-beam delay.

96. The system of any one of claims 73-95, wherein the waveform has a voltage amplitude of 500 to 4,000 volts.

97. The system of any of claims 73-96, wherein the waveform has a frequency of 300-800 kHz.

98. The system of any one of claims 73-97, wherein each of the one or more packets has 10-200 biphasic pulses.

99. The system of any one of claims 73-97, wherein each of the one or more packets has 20-50 biphasic pulses.

100. The system of any of claims 73-99, wherein the treatment comprises 5 to 100 packets.

101. The system of any of claims 73-99, wherein the treatment comprises 10 to 60 packets.

102. The system according to any of claims 73-101, further comprising a remotely-dispensing electrode positionable so as to deliver said energy in a monopolar fashion.

103. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated by a waveform comprising at least one packet of pulses for providing the therapy, wherein each pulse has a pulse length and at least one of the at least one packet comprises a delay having a delay period that is at least twice the pulse length.

104. The system of claim 103, wherein the delay period is at least ten times the pulse length.

105. The system of any of claims 103-104, wherein the at least one packet has a packet length that is at least 50 times the delay period.

106. The system of claim 105, wherein the at least one packet has a packet length that is at least 100 times the delay period.

107. The system of any of claims 103-106, wherein the delay comprises an inter-pulse delay.

108. The system of claim 107, wherein the pulses are biphasic pulses and the inter-pulse delay is an inter-period delay.

109. The system of any of claims 103-106, wherein the pulse is a biphasic pulse and the delay comprises an inter-phase delay.

110. The system of any one of claims 103-109, wherein the delay period comprises 250 to 1000 microseconds.

111. The system of any of claims 103-110, wherein the at least one packet comprises at least 25 pulses.

112. The system of claim 111, wherein the at least one packet comprises at least 40 pulses.

113. The system of any one of claims 103-112, wherein the at least one packet is separated from an adjacent packet by an inter-packet delay of at least 30 microseconds.

114. The system of claim 113, wherein the at least one packet is separated from adjacent packets by an inter-packet delay of 100-5000 microseconds.

115. The system of any of claims 103-114, wherein the treatment comprises 5-100 packets.

116. The system of claim 115, wherein the treatment comprises 10-60 packets.

117. The system of any one of claims 103-116, wherein the waveform has a voltage magnitude of 500-10,000 volts.

118. The system of any of claims 103-117, wherein each pulse has a pulse length of 1.66 microseconds.

119. The system of any of claims 103-117, wherein each pulse has a pulse length of 2.5 microseconds.

120. The system of any of claims 103-117, wherein each pulse has a pulse length of 20 microseconds.

121. The system according to any of claims 103-120, further comprising a remotely located dispersive electrode positionable so as to deliver said energy in a monopolar fashion.

122. The system of any one of claims 103-121, wherein the delay period has a length sufficient to reduce or avoid bubble formation near the at least one electrode.

123. The system of any of claims 103-122, wherein the delay period is of sufficient length to reduce or avoid a discharge event in the vicinity of the at least one electrode.

124. The system of any of claims 103-123, wherein the delay period is of sufficient length to reduce or avoid cavity formation in the tissue.

125. The system of any one of claims 103-124, wherein the delay period is of sufficient length to reduce or avoid muscle contraction in the patient.

126. The system of any of claims 103-125, wherein the delay period is of sufficient length to be sufficient in length

Avoiding peak temperatures in the tissue that may have been reached by the delivery of the energy without the one or more delay periods.

127. The system of claim 126, wherein the peak temperature causes bubble formation.

128. The system of any one of claims 126-127, wherein the peak temperature is 100 degrees celsius.

129. The system of any one of claims 126-128, wherein the peak temperature causes an electrical discharge.

130. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated from a waveform comprising at least one package of biphasic pulses for providing the therapy, wherein each biphasic pulse comprises an inter-phase delay in the range of 250 to 1000 microseconds.

131. The system of claim 130, wherein the waveform has a voltage amplitude of 500-10,000 volts.

132. The system of any of claims 130-131, wherein each pulse has a pulse length of 1.66 microseconds.

133. The system of any of claims 130-131, wherein each pulse has a pulse length of 2.5 microseconds.

134. The system of any of claims 130-131, wherein each pulse has a pulse length of 20 microseconds.

135. The system of any of claims 130-134, wherein the delay period has a length sufficient to reduce or avoid bubble formation near the at least one electrode.

136. The system of any of claims 130-135, wherein the delay period is of sufficient length to reduce or avoid a discharge event in the vicinity of the at least one electrode.

137. The system of any of claims 130-136, wherein the delay period has a length sufficient to reduce or avoid void formation in the tissue.

138. The system of any of claims 130-137, wherein the delay period is of sufficient length to reduce or avoid muscle contraction in the patient.

139. The system of any of claims 130-138, wherein the delay period is of sufficient length to enable the delay period to be sufficient in length

Avoiding a peak temperature in the tissue that would be reached by the delivery of the energy without the one or more delay periods.

140. The system of claim 139, wherein the peak temperature causes bubble formation.

141. The system of any of claims 139-140, wherein the peak temperature is 100 degrees celsius.

142. The system of any of claims 139-141, wherein the peak temperature causes a discharge.

143. The system of any of claims 130-142, further comprising a remotely-located dispersive electrode positionable so as to deliver the energy in a monopolar fashion.

144. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated by a waveform comprising 2-60 packets of pulses for providing the therapy, wherein each packet comprises at least one delay period in the range of 250 to 1000 microseconds.

145. The system of claim 144, wherein the waveform has a voltage amplitude of 500-10,000 volts.

146. The system of any of claims 144-145, wherein each pulse has a pulse length of 1.66 microseconds.

147. The system of any of claims 144-145, wherein each pulse has a pulse length of 2.5 microseconds.

148. The system of any of claims 144-145, wherein each pulse has a pulse length of 20 microseconds.

149. The system of any of claims 144-148, wherein the delay period is of sufficient length to reduce or avoid bubble formation in the vicinity of the at least one electrode.

150. The system of any of claims 144-149, wherein the delay period is of sufficient length to reduce or avoid a discharge event in the vicinity of the at least one electrode.

151. The system of any of claims 144-150, wherein the delay period is of sufficient length to reduce or avoid cavity formation in the tissue.

152. The system of any of claims 144-151, wherein the delay period is of sufficient length to reduce or avoid muscle contraction in the patient.

153. The system of any of claims 144-152, wherein the delay period is of sufficient length to be sufficient in length

Avoiding a peak temperature in the tissue that would be reached by the delivery of the energy without the one or more delay periods.

154. The system of claim 153, wherein the peak temperature causes bubble formation.

155. The system of any of claims 153-154, wherein the peak temperature is 100 degrees celsius.

156. The system of any of claims 153-155, wherein the peak temperature causes a discharge.

157. The system of any of claims 144-156, further comprising a remotely positionable dispersive electrode for delivering the energy in a monopolar fashion.

158. A system for treating a tissue of a patient, comprising:

at least one electrode positionable adjacent tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated from a waveform comprising at least one pulse packet having a delay period, wherein the at least one packet has a packet length that is at least 50 times the delay period.

159. The system of claim 158, wherein the at least one packet has a packet length that is at least 100 times the delay period.

160. The system of any one of claims 158-159, wherein each pulse has a pulse length of 1.66 microseconds.

161. The system of any one of claims 158-159, wherein each pulse has a pulse length of 2.5 microseconds.

162. The system of any of claims 158-159, wherein each pulse has a pulse length of 20 microseconds.

163. The system of any of claims 158-162, wherein the delay period has a length sufficient to reduce or avoid bubble formation near the at least one electrode.

164. The system of any one of claims 158-163, wherein the delay period is of sufficient length to reduce or avoid a discharge event in the vicinity of the at least one electrode.

165. The system of any of claims 158-164, wherein the delay period is of sufficient length to reduce or avoid cavity formation in the tissue.

166. The system of any of claims 158-165, wherein the delay period is of sufficient length to reduce or avoid muscle contractions in the patient.

167. The system of any of claims 158-166, wherein the delay period is of sufficient length to avoid a peak temperature in the tissue that would be reached by the delivery of the energy without the one or more delay periods.

168. The system of claim 167, wherein the peak temperature causes bubble formation.

169. The system of any of claims 167-168, wherein the peak temperature is 100 degrees celsius.

170. The system of any of claims 167-169, wherein the peak temperature causes an electrical discharge.

171. The system of any of claims 167-170, further comprising a remotely-dispensing electrode positionable so as to deliver the energy in a monopolar fashion.

172. A system for treating a tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated by a waveform comprising at least one pulse packet, wherein a duty cycle of each pulse is less than or equal to 50% so as to reduce or avoid one or more secondary effects.

173. The system of claim 172, wherein the one or more secondary effects comprise cavity formation in the tissue.

174. The system of claim 172, wherein a duty cycle of each pulse is less than or equal to 20%.

175. The system of claim 174, wherein the one or more secondary effects comprise a discharge event.

176. The system of claim 172, wherein a duty cycle of each pulse is less than or equal to 2.5%.

177. The system of claim 176, wherein the one or more secondary effects comprise bubble formation.

178. The system of claim 177, wherein the bubble formation comprises formation of bubbles having a diameter greater than or equal to 0.1 mm.

179. A system for treating tissue, comprising:

an electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, wherein the energy is generated from a waveform having a specific delay period between selected pulses to affect gas formation, external electrical discharge, muscle contraction, cavity formation, and/or temperature elevation.

180. A method of affecting at least one secondary effect of pulsed electric field therapy, comprising:

a particular delay period is selected between portions of the pulsed electric field waveform to affect the at least one secondary effect.

181. The method of claim 1, wherein the at least one secondary effect comprises gas formation.

182. The method of claim 1, wherein the at least one secondary effect comprises an electrical discharge.

183. The method of claim 1, wherein the at least one secondary effect comprises cavity formation.

184. The method of claim 1, wherein the at least one secondary effect comprises a muscle contraction.

185. The method of claim 1, wherein the at least one secondary effect comprises a temperature increase.

These and other embodiments are described in further detail below in connection with the accompanying drawings.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features believed characteristic of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

fig. 1 illustrates an embodiment of a pulsed electric field waveform having pulses that are monophasic and separated by an inter-pulse delay measured from one pulse of a polarity to the next pulse of the same polarity.

Fig. 2 illustrates an embodiment of a pulsed electric field waveform with biphasic pulses, where each cycle consists of one polarity pulse followed by an opposite polarity pulse.

Fig. 3 illustrates an embodiment with a pulsed electric field waveform such as the biphasic pulses in fig. 2, however in this embodiment the opposite polarity pulses are separated by an interphase delay.

Fig. 4 illustrates example pulses grouped in strings or packets.

FIG. 5 illustrates an example packet grouped into batches or bundles.

Fig. 6A-6C provide ultrasound images illustrating bleb formation under various conditions when the energy delivery body is submerged in a saline bath.

Fig. 7A-7B illustrate example comparisons between the effects of different sized cycle delays on discharge.

Figures 8A-8B illustrate the effect of an equivalent pulsed electric field treatment regimen delivered to liver tissue, except for different cycle delays. Fig. 8A illustrates the results of using a waveform with a period delay of about 50ns, which results in a significant tissue cavity format. Figure 8B illustrates the result of using the same waveform but with a period delay of about 1000 mus.

FIG. 9 illustrates the Langerhans' knot (Nodes of Ranvier) occurring along myelinated axons, with the axonal membrane (axonal membrane) exposed to the extracellular space.

Fig. 10 illustrates a model that models a myelinated axonal region as an electrical component.

Fig. 11A-11D illustrate the charging and discharging behavior of a motor neuron in response to a pulsed electric field waveform with no or low cycle delay and large cycle delay.

Figure 12 illustrates the effect of cycle delay on muscle stimulation threshold.

Figure 13 illustrates the magnitude and distribution of temperature increase from the pulsed electric field scheme generated by numerical simulation.

Fig. 14A to 14B illustrate temperature distributions at the time of maximum temperature increase associated with fig. 13.

Figure 15 provides an overview illustration of an example therapy system for delivering dedicated pulsed electric field energy.

Figure 16 illustrates another embodiment of a treatment device configured to deliver specialized pulsed electric field energy, particularly configured to deliver focal therapy (focal therapy).

Fig. 17 illustrates a portion of a heart showing a cross-sectional view of the right atrium and left atrium along with the treatment apparatus of fig. 16 disposed therein.

Fig. 18 illustrates the use of the treatment device of fig. 16 to treat tissue surrounding the opening of the lower left pulmonary vein in a point-by-point manner.

Fig. 19A-19B illustrate another embodiment of a therapeutic energy delivery catheter or device.

Fig. 20A-20B illustrate another embodiment of a treatment system.

Fig. 21A illustrates an embodiment of a signal waveform specified by an energy delivery algorithm.

Fig. 21B illustrates various examples of biphasic pulses with inter-phase times therebetween.

Fig. 21C illustrates a further example of waveforms having unequal voltages.

Fig. 21D illustrates a further example of waveforms having unequal pulse widths.

Fig. 21E illustrates an example waveform specified by another energy delivery algorithm, where the waveform is monophasic.

Fig. 21F illustrates a further example of a waveform with monophasic pulses.

Fig. 21G illustrates a further example of a waveform having such a phase imbalance.

Fig. 21H illustrates an example of a waveform having an imbalance in both the positive voltage and the negative voltage.

Fig. 22 is a graph illustrating a partial sample Electrocardiogram (ECG) trace of a human heart during highlighting, where it is desired to deliver an energy pulse to a pulmonary channel via an energy delivery body.

Detailed Description

Specific embodiments of the disclosed apparatus, system, and method will now be described with reference to the accompanying drawings. Nothing in this detailed description is intended to imply that any particular component, feature, or step is essential to the invention.

A variety of different types of energy have been used for therapeutic treatment of patients, including Radiofrequency (RF) energy, microwave (MW) energy, high Intensity Focused Ultrasound (HIFU) energy, and Pulsed Electric Field (PEF) energy, to name a few. These energy patterns differ depending on the waveform of the electrical signal provided by the generator. They are classified, if possible, according to the electromagnetic spectrum. The electromagnetic spectrum covers a frequency range from below 1 Hz to above 10 Hz²⁵ Hertz, which corresponds to wavelengths from thousands of kilometers to a fraction of the size of a nucleus. This frequency range is divided into various bands, the electromagnetic waves within each frequency being given different names; starting from the low frequency (long wavelength) end of the spectrum, they are: radio waves, microwaves, terahertz waves, infrared rays, visible light, ultraviolet rays, X-rays, and gamma rays at the high frequency (short wavelength) end. The electromagnetic waves in each of these bands have different characteristics, such as how they are generated, how they interact with matter, and their practical application.

RF energy is the lowest portion of the electromagnetic spectrum and is well known as the medium for analog and modern digital wireless communication systems. It propagates in the range between 3kHz and 300GHz and is a continuous waveform. Waveforms having frequencies in the RF range have been manipulated from continuous waveforms to pulsed waveforms. Thus, energy is applied intermittently in pulses or bursts. The effect of pulsed RF or Pulsed Electric Field (PEF) on cellular tissue is different from continuous delivery of RF because cells react differently during the time energy is applied. For example, RF ablation causes cell death due to thermal damage to the cells, while PEF causes cell death by non-thermal (i.e., below the threshold that causes thermal ablation) effects. Such cell death maintains the extracellular matrix so that the target tissue maintains its structural architecture, including blood and lymphatic vessels. Thus, sensitive structures, such as biological lumens, blood vessels, nerves, etc., can be preserved, which is critical to maintaining the integrity and functionality of the tissue.

Fig. 1 illustrates an embodiment of a PEF waveform 10 having pulses 12 that are monophasic and separated by an inter-pulse delay 14 measured from one pulse of polarity to the next pulse of the same polarity. Thus, the inter-pulse delay 14 may be considered a DC pulse delay. Fig. 2 illustrates an embodiment of a PEF waveform 10 having two pulses 12, each pulse 12 being biphasic, with each cycle consisting of one polarity phase 12a followed by an opposite polarity phase 12 b. In this embodiment there is no delay between the two opposite polarity phases 12a, 12b, but there is an inter-period delay 16 between periods (i.e. a biphasic pulse). It will be appreciated that an inter-period delay is one form of inter-pulse delay in which the pulses are biphasic pulses. Fig. 3 illustrates an embodiment of a PEF waveform 10 having a biphasic pulse 12 such as in fig. 2, however in this embodiment the opposite polarity phases 12a, 12b are separated by a switching or interphase delay 18.

In some cases, the pulses 12 are grouped into strings or packets 20, such as illustrated in fig. 4. Here, five packets 20 are illustrated, each packet 20 consisting of a plurality of cyclic or biphasic pulses. The packets 20 are separated by an inter-packet delay 22. It is understood that the packet 20 may be composed of various types of pulses (e.g., monophasic, biphasic, etc.) and of the same or different polarities. For example, in some embodiments, the packet 20 consists of a series of pulses 12 of the same polarity, followed by a polarity switch of one or more pulses 12, which may or may not be followed by a polarity switch of one or more additional pulses 12.

Optionally, in some cases, the packets 20 are grouped into batches or bundles 24, such as illustrated in fig. 5. Here, two bundles 24 are shown, each bundle 24 consisting of three packets 20. The beams 24 are separated by an inter-beam delay 26. Typically, energy is applied to the patient such that the inter-beam delay 26 is synchronized with the heartbeat, wherein the inter-beam delay 26 occurs during sensitive portions of the heartbeat. Thus, energy is applied outside the sensitive parts of the heartbeat to avoid inducing arrhythmias. In some embodiments, energy is delivered during the R-T interval of the patient's ECG rhythm. In other embodiments, PEF energy is delivered to an unknown location in the ECG waveform. In particular, biphasic waveforms can be safely delivered in this manner without disrupting the normal electrophysiological behavior of the heart. Thus, a beam may be used for reasons such as accelerated therapy, with different inter-beam delays 26 created for other reasons such as thermal mitigation. Alternatively, the packages 20 may be delivered in rapid succession without having to bundle the packages. These packets may be delivered to the ECG rhythm synchronously or asynchronously.

Generally, treatment is considered to be the period during which energy is delivered to a target zone before moving to the next target zone. For example, when treating a pulmonary tract, the energy delivery device may include an electrode that circumferentially contacts an inner surface of a segment of the pulmonary tract. The energy from the waveform may be applied continuously, or the user may start and stop energy activation/application. In either case, energy is delivered to the electrodes until the targeted tissue segment receiving the energy is desirably treated. The energy delivery is then stopped, and the electrode is repositioned within the lung passageway to treat a new target tissue section (with or without overlap with the first section of target tissue). Each period of energy delivery to a target zone before moving to the next target zone is considered a treatment. Thus, patients typically undergo multiple treatments in the lungs during surgery.

When treating a portion of the heart, such as when ablating a portion of the heart to treat atrial fibrillation, the energy delivery device may include an electrode having a blunt tip that contacts a surface of the atrium or pulmonary vein. In this case, energy is delivered from the tip to the heart tissue to produce ablation at the contact region. This operation is repeated as the tip is moved to a different position to produce a circular or linear ablation to prevent electrical conduction through the heart tissue. Likewise, treatment is considered to be the period of energy delivery to the target area before moving to the next target area. Thus, a total block will typically involve multiple treatments, where each treatment consists of one or more activations.

In summary, for the purposes described herein, treatment generally includes the entire period of PEF delivery delivered from one electrode (or set of electrodes) to another electrode (or set of electrodes) prior to moving one of the electrodes to affect the target tissue segment. Also, activation typically includes delivery of PEF therapy for a single "start" sequence initiated by the user. Multiple activations can be delivered in a single treatment. The time between activations will be determined by the user and any secondary limitations of PEF delivery, such as synchronization with the heart rhythm, time to return the temperature to baseline, or occasional incomplete therapy delivery due to first activation.

The PEF waveform is delivered to the tissue by one or more energy delivery bodies, each having one or more electrodes. Finally, the physical arrangement of the electrodes forms an electrical circuit. The electrodes may act as cathodes or anodes, or both, at any given time within a packet, a series of pulses, a cycle, an activation, or any other period separating two pulses. When the electrodes that partially or fully generate the circuit are in the same regional proximity, particularly in or near the target tissue, the system is referred to as a bipolar or multipolar electrode arrangement. When more than two polarity orientations are used, a multipole arrangement will be applied, such as one electrode set to 1000V, a second electrode set to 500V, and a third electrode set to 0V, so the second electrode is known to be the negative polarity of the first electrode, but the positive polarity of the third electrode. When one or more of the circuit electrodes are separately placed at a remote non-target region of tissue (e.g., a discrete pad), such an arrangement is referred to as a monopolar electrode arrangement. These descriptions are for convenience, and descriptions of using concepts described herein for any of these arrangements may be construed as applicable to other electrode arrangements.

The energy delivery may be driven by a variety of mechanisms, such as using a driver 132 on the device 102 or a foot switch operably connected to the generator 104. Such actuation typically provides a single energy dose or activation. The energy dose is generally limited by the number of packets delivered and the packet voltage. Each energy dose delivered to the target tissue is configured to maintain a temperature at or in the target tissue below a threshold for thermal ablation, particularly thermal ablation or denaturation of matrix proteins in the basement membrane or deeper submucosal extracellular protein matrix. In addition, the dosage can be adjusted or moderated over time to further reduce or eliminate heat buildup during the treatment procedure. The energy dose is not to induce thermal damage (defined as extracellular protein coagulation at a site at risk for treatment), but rather to provide energy at a level that induces treatment of the condition without damaging sensitive tissues.

It will be appreciated that the delays described herein (e.g., inter-pulse delay 14, inter-period delay 16, inter-phase delay 18, inter-packet delay 22, inter-beam delay 26, etc.) may be consistent or variable throughout the packet 20, the beam 26, and/or the treatment depending on the waveform type. Also, some delays may not be present because they are zero or because they are not correlated with the waveform (e.g., if there is no beam 24, there is no inter-beam delay 26 because it is not correlated). The inter-pulse delays 14 may be consistent throughout the packets 20 of pulses 12, or they may vary over the course of the packets 20. For example, a first inter-pulse delay may be 50ns, followed by a second inter-pulse delay of 1ms, after which the sequence repeats. There may be sub-patterns within the package 20 in which a given sequence of pulses 12 of varying polarity (e.g., up, down, delay, up, down \8230; up, down, up, delay, down, up, down, 8230; etc.) is repeated, these sub-patterns being referred to as a series of pulses. Each pulse train has the same pattern, which defines it as a train. However, each series may have different characteristics, such as pulses with different polarities, different pulse widths, different amplitudes, and different inter-phase and/or inter-pulse delays in different modes. In some embodiments, different series are positioned in a repeating sequence, so that, in some embodiments, there is a correlated inter-series delay from any given pulse to a subsequent pulse, and a sub-range of inter-series delays between given series.

In some embodiments, the inter-pulse delay 14 is uniform over the course of the packet 20, while in other embodiments, the inter-pulse delay 14 varies within the packet 20. In some embodiments, the duty cycle of the pulses comprising the packet ranges from <0.01% to 100%. In some embodiments, the treatment includes equal packets 20, where each packet 20 has a uniform inter-pulse delay 14 or a non-uniform inter-pulse delay 14. In other embodiments, the treatment includes at least two different types of packets 20, wherein each of the at least two different types of packets 20 has a uniform inter-pulse delay 14, and the inter-pulse delay 14 differs between the at least two different types of packets 20. Or in other embodiments, at least one of the at least two different types of packets 20 has a different non-uniform inter-pulse delay than the other. In general, when beam 24 is present, the inter-beam delay 26 is consistent when synchronized to the heart rhythm, however it is understood that the inter-beam delay 26 may vary as the patient's heart rhythm varies or as other therapy delivery regimen constraints dictate.

In any case, it will be appreciated that any combination of delays (e.g., inter-pulse delay 14, inter-cycle delay 16, inter-phase delay 18, inter-packet delay 22, inter-beam delay 26, etc.) may be utilized within the treatment to achieve the desired results. In particular, these delays may be specifically manipulated to achieve certain desired results. For example, one, some, or all of these delays may be operated to control various aspects of PEF therapy to mitigate any associated risks, such as gas formation, electrical discharges, cavity formation, muscle contraction, and temperature rise, to name a few. In some embodiments, delaying the period of distributed (high) voltage PEF energy delivery results in significant variation and optimization of the therapy delivery results. In some embodiments, the delay described herein ranges between 0s and 100 ms.

In some embodiments, the delay period is operated to apportion the rate of energy delivery and allow the resolution and decay of certain effects prior to the delay period, thereby inducing effects from their accumulation. When PEFs are applied to biological cell and tissue operations, the therapeutic effect can be accumulated on the cells by multiple cycles or a series of pulses when the time scale of charge accumulation and decay is different from other effects, but without causing various secondary therapeutic effects such as gas formation, electrical discharges, cavity formation, muscle contraction, and temperature increase, to name a few. In other cases, these secondary cumulative therapeutic effects may be desirable to initiate or enhance therapeutic outcomes, and therefore delays will be selected to promote these effects, again with the primary objective of not altering the response of the induced cells and tissues to PEF. These examples of secondary effects are not an exhaustive list, and secondary effects of other desired operations may also be controlled by selecting an appropriate delay.

Gas formation

In some embodiments, the delay is operated to prevent the formation of gases generated by PEF therapy. As mentioned previously, energy needs to be delivered for a sufficient period of time in order to break molecular bonds, thereby forming a gas. Furthermore, once the gas forms, it will over time aggregate and merge into a generally larger area, forming progressively larger bubbles. The larger the bubble, the longer the time it takes for the bubble to reabsorb into the fluid. By skillfully introducing a delay into the waveform, these processes can be reduced or avoided. Such a delay provides energy for a period of time that is insufficient to form any or any significant amount of gas and/or insufficient to allow any bubbles that may be generated to become large enough to avoid dissolution. The total energy delivered is not altered by such delay operations, thereby maintaining the overall therapeutic effect. Thus, by choosing the delay correctly, it is possible to avoid gas formation or complete re-dissolution of bubbles or re-formation of other molecules.

Even if the delay is not sufficient to completely eliminate the gas by absorption into the fluid, the delay may be sufficient to prevent the gas from meaningfully collecting as larger bubbles. In this case, the smaller bubbles are relaxing and begin to absorb before the next energy start and additional gas formation. In this way, the bubbles do not coalesce into large bubbles. Importantly, the size of the bubble is also related to its effect in vivo. A small (diameter <0.1 mm) bubble will typically absorb in the order of seconds and is typically too small to induce a meaningful ischemic event. Thus, bubbles produced in this size generally do not pose a significant threat to patient safety. In contrast, larger bubbles (> 0.1 mm) may take several minutes or more to absorb and may damage or occlude the vessel. Thus, even if bubble generation cannot be completely eliminated, it may be equally effective to suppress the size and number of bubbles produced to only those bubbles that are clinically insignificant and/or that will quickly absorb.

In some embodiments, when PEF therapy is delivered in blood (electrolyte) in a monopolar fashion (i.e., with a remotely located return electrode) using a 7F tip cardiac ablation focused electrode catheter, the inhibition of the amount and magnitude of gas production formation may begin to intervene when there is a 1 μ s period delay in the waveform of pulse 12 with biphasic (1 μ s duration) and a voltage of 3000V. In other embodiments, comparable energy delivery begins to show a significant reduction in gas formation when the cycle delay is 10 or 20 μ s, with a complete elimination of hyperechoic bubbles when the cycle delay is greater than or equal to 150 μ s.

Fig. 6A-6C provide ultrasound images illustrating bleb formation under various conditions when the energy delivery body 108 (e.g., electrodes) is submerged in a saline bath. Fig. 6A illustrates a baseline image of the energy delivery body 108, indicated by arrows, in which no energy is delivered. Thus, the image was used as a control. Shading artifacts are highlighted at the arrows. Fig. 6B illustrates energy delivered by energy delivery body 108, where the waveform has a period delay of 50 ns. This shows a large number of hyperechoic bubbles with the generated pie visualized on the screen. Fig. 6D illustrates energy delivered by energy delivery body 108, where the waveform has the same parameters as in fig. 6B, but the waveform has a period delay of 1 ms. As shown, no bubbles are visible anywhere within the imaging window.

Thus, in some embodiments, when delivering PEF therapy in blood or any electrolyte adjacent to the target tissue, such as in cardiac or vascular clinical applications, gas formation may be eliminated using a delay (such as a cycle delay or other delay in the range of 100 μ s-10,000 μ s, preferably 100 μ s-1000 μ s, such as 250 μ s-1000 μ s). It will be appreciated that in some embodiments the delay is in the range 100 μ s, 150 μ s, 200 μ s, 250 μ s, 300 μ s, 400 μ s, 500 μ s, 600 μ s, 700 μ s, 800 μ s, 900 μ s, 1000 μ s, 100-250 μ s, 250-500 μ s, 500-1000 μ s, greater than 250 μ s, greater than 500 μ s, greater than 1000 μ s, 1000-5,000 μ s, 1000-10,000 μ s, to name a few. In some embodiments, when delivering PEF to solid tissue, such as when the energy delivery body 108 is positioned into target tissue, gas formation may be eliminated using a delay (such as a period delay or other delay in the range of 10 μ s-1000 μ s, preferably 25 μ s-100 μ s). It will be appreciated that in some embodiments the retardation is 10 μ s, 20 μ s, 25 μ s, 30 μ s, 40 μ s, 50 μ s, 60 μ s, 70 μ s, 80 μ s, 90 μ s, 100 μ s, in the range 10-100 μ s, 25-500 μ s, 500-1000 μ s, greater than 25 μ s, greater than 50 μ s, greater than 100 μ s, to name a few.

Discharge of electricity

In some cases, when energy is delivered from the energy delivery body 108 to the patient, current is concentrated and concentrated in the focal region around the energy delivery body 108. At some point, the accumulated energy delivery exceeds the decomposition potential of the energy delivery body 108 material or surrounding tissue or fluid. This causes a discharge event (e.g., a sudden current, such as an arc) from the energy delivery body 108 to nearby tissue, fluid, or cells. However, introducing an appropriate waveform delay allows for relaxation of charge accumulation in the fluid and tissue material. Thus, by introducing a delay, energy delivery is not constant, thus allowing charge accumulation to be relaxed at various times before energy delivery is resumed. With a sufficient number and duration of delays, discharge events can be prevented. A sufficient amount and duration of delay to prevent discharge is related to the energy and intensity of the treatment regimen; higher voltages will involve longer delays.

The discharge event is likely to be present in PEF therapy involving waveforms having voltages in the range of 500-5000V to elicit its therapeutic effect, particularly when a bipolar electrode arrangement is used. It will be appreciated that depending on the particular conditions, a discharge event may occur outside of this range, particularly when energy is delivered via the bipolar electrode. For these parameter ranges, delays of 50, 250, 500, or 1000 μ s and above (e.g., cycle delays, etc.) may be most appropriate to maintain a predominant degree of therapeutic effect while preventing arcing.

Fig. 7A-7B illustrate example comparisons between the effects of different sized cycle delays on discharge. Here, the energy delivery body 108 is immersed in a saline bath and delivers PEF therapy until a visible electrical discharge is encountered. The waveform consists of a plurality of pulses 12, the plurality of pulses 12 forming a packet 20 having a conduction time of 300 mus. The 300 mus on time packet is delivered at a gradually increasing voltage until a visible discharge event is encountered. After this the on-time is decreased and the voltage continues to increase until the discharge is seen again. Fig. 7A illustrates a waveform with a very small period delay (50 ns). Fig. 7B illustrates a waveform with a moderate period delay (50 μ s). Notably, the 50 μ s cycle delay test set shows that there is a 78% increase in the possible delivered ground current before a discharge is noted, as compared to a very small-50 ns cycle delay. Thus, this modest cycle delay has been demonstrated to significantly increase the amount of energy that the electrode can deliver prior to discharge. This cycle delay is well below the range where a reduction in therapeutic effect is likely to be encountered (most likely starting to occur within the 5-10ms cycle delay range, depending on cell size and nature). This greater resilience to arcing proved to be maintained for all packet on times tested in this series.

It is understood that the design of energy delivery bodies 108 or the physical arrangement of energy delivery bodies 108 also plays a role. When the design or placement of the energy delivery bodies 108 promotes current concentration, such as smaller contact areas or sharp boundary regions on the energy delivery bodies 108, longer delays are utilized to mitigate discharge events.

Thus, in some embodiments, when delivering PEF therapy in blood or any electrolyte adjacent to the target tissue, such as in cardiac or vascular clinical applications, the discharge may be eliminated using a delay (such as a cycle delay or other delay in the range of 50 μ s-10,000 μ s, preferably 250 μ s-1000 μ s). It will be appreciated that in some embodiments the retardation is in the range 50 μ s, 100 μ s, 150 μ s, 200 μ s, 250 μ s, 300 μ s, 400 μ s, 500 μ s, 600 μ s, 700 μ s, 800 μ s, 900 μ s, 1000 μ s, 50-250 μ s, 250-500 μ s, 500-1000 μ s, greater than 250 μ s, greater than 500 μ s, greater than 1000 μ s, 1000-5,000 μ s, 1000-10,000 μ s, to name a few. In some embodiments, when delivering PEF to solid tissue, such as when energy delivery volumes 108 are positioned to target tissue, the electrical discharge may be eliminated using a delay (such as a cycle delay or other delay in the range of 100 μ β -10,000 μ β, preferably 250 μ β -2000 μ β). It will be appreciated that in some embodiments the retardation is in the range of 100 μ s, 200 μ s, 250 μ s, 300 μ s, 400 μ s, 500 μ s, 600 μ s, 700 μ s, 800 μ s, 900 μ s, 1000 μ s, 1500 μ s, 2000 μ s, 250-500 μ s, 250-1000 μ s, 500-1000 μ s, greater than 250 μ s, greater than 500 μ s, greater than 1000 μ s, to name a few. In some embodiments, when delivering PEF to a luminal target (e.g., an airway), such as when energy delivery body 108 is positioned within a lumen of a target tissue without an electrically conductive fluid, the electrical discharge may be eliminated using a delay (such as a cycle delay or other delay in the range of 10 μ β -10,000 μ β, preferably 50 μ β -500 μ β). It will be appreciated that in some embodiments the retardation is in the range of 10 μ s, 20 μ s, 30 μ s, 40 μ s, 50 μ s, 60 μ s, 70 μ s, 80 μ s, 90 μ s, 100 μ s, 200 μ s, 300 μ s, 400 μ s, 500 μ s, 50-100 μ s, 100-250 μ s, 250-500 μ s, 1000-10,000 μ s, greater than 50 μ s, greater than 250 μ s, greater than 500 μ s, greater than 1000 μ s, to name a few.

Cavity formation

As mentioned, when an electrical discharge does occur, a pressure wave is generated that is visibly noticeable as an audible "pop". When the electrical discharge and the pressure wave have sufficient intensity and repeat a sufficient number of times, the energy transferred from the pressure wave and deposited into the tissue can severely damage the tissue architecture and cells. The effect thereby produced is the cumulative creation of defects or cavities within the tissue at the region near the electrodes, which region experiences these effects of maximum intensity.

By adding a delay between the energized portions of the waveform (such as within a PEF packet), time is allowed to resolve the physical effects at the molecular level before these effects accumulate into pressure waves that can generate tissue cavities. This results in a more distributed deposition of energy into the tissue, reducing or eliminating the pressure waves that occur as a result of PEF therapy. Thus, the introduction of periodic and other delays in the waveform may be used to mitigate or eliminate cavity generation. This can be exploited to increase the predictability of the outcome of the therapeutic effect and can also be used to eliminate risks associated with cavity formation, such as disruption of vasculature integrity, fistula formation, or damage to other sensitive tissues.

Fig. 8A-8B illustrate the effect of an equivalent PEF treatment regimen delivered to liver tissue T, except for different cycle delays. Fig. 8A illustrates the results of using a waveform with a period delay of about 50ns, which results in a significant tissue cavity C format. Figure 8B illustrates the result of using the same waveform but with a period delay of about 1000 mus. Thus, the same amount of energy is delivered. As shown, such a longer period delay can completely eliminate the large cavities formed in the liver tissue T.

One side benefit of cavity elimination is more efficient deposition of energy into the tissue by potentially eliminating gaps at the tissue-electrode interface. This may result in greater therapeutic effect.

In some embodiments, when delivering PEF to solid tissue, such as when the energy delivery body 108 is positioned to the target tissue, cavity formation may be eliminated by using a delay (such as a period delay or other delay in the range of 100 μ s-10,000 μ s, preferably 250 μ s-2000 μ s). It will be appreciated that in some embodiments the retardation is in the range 100 μ s, 200 μ s, 250 μ s, 300 μ s, 400 μ s, 500 μ s, 600 μ s, 700 μ s, 800 μ s, 900 μ s, 1000 μ s, 1500 μ s, 2000 μ s, 250-500 μ s, 250-1000 μ s, 500-1000 μ s, 1000-2000 μ s, greater than 250 μ s, greater than 500 μ s, greater than 1000 μ s, to name a few.

Contraction of muscles

In PEF therapy, the cells and tissues closest to the energy delivery bodies 108 are the most severely affected cells and tissues. It is possible to subject these cells and tissues to cumulative therapeutic effects while avoiding or preventing the generation of action potentials in distant motor neurons and skeletal muscle (as well as cardiac and smooth muscle). This is achieved by using biphasic pulses and is further achieved by delays within the waveform. It has been found that the charging and relaxation properties of these distant motor neurons involve a longer duration of cycle delay to prevent their occurrence. For example, a periodic delay of 10ms, 20ms, 30ms, 40ms, or 50ms may be used.

In some implementations, the desired cycle delay is determined at least in part by numerical simulation of action potential generation. In some embodiments, the model used is based on a Langerhans' knot array between myelinated regions of axons. Referring to fig. 9, the lanugo knot NR, also known as the myelin space, occurs along myelinated axon MA, with axonal membrane AA (axonal membrane) exposed to the extracellular space. The Langmuir junctions NR are uninsulated and highly enriched in ionic channels, enabling them to participate in the ion exchange required for regenerating action potentials. Nerve conduction in myelinated axons MA occurs in a manner in which action potentials appear to "hop" along the axon MA from one node NR to the next. This results in faster conduction of the action potential.

Referring to fig. 10, the myelinated axon MA region was modeled as a resistor for the intracellular environment. Each node NR consists of a cell membrane that separates the intracellular environment from the extracellular environment and is modeled as a capacitor in parallel with a leakage resistance and a voltage source. When exposed to an electric field, myelinated axons MA begin to charge up along the capacitor. When the electric field is removed (e.g., the pulse stops for a delay period), the charge accumulation on the myelinated axon MA begins to discharge. Thus, the ability of PEF therapy to induce action potentials in motor neurons is related to the effective duty cycle of the PEF waveform.

This concept is expressed in fig. 11A to 11D. Fig. 11A illustrates an example PEF waveform 10 with no or low cycle delay 16, while fig. 11B illustrates a schematic depiction of the charging 62 and discharging 64 behavior of a motor neuron. Two packets 20 of waveform 10 are depicted separated by an inter-packet delay 22. When the package 20 is delivered, the motor neurons are gradually charged throughout the delivery process. Over time, the accumulated transmembrane potential induces an action potential (indicated by dashed line 66). The motor neuron then begins to discharge at the beginning of the inter-packet delay 22. This is repeated for each subsequent packet 20.

Fig. 11C illustrates an example PEF waveform 10 having a greater cycle delay 16 than the waveform of fig. 11A. Fig. 11D provides a schematic depiction of the charging 62 and discharging 64 behavior of a motor neuron. When waveform 10 is delivered, the motor neurons are gradually charged throughout the delivery process, however the discharge begins at the beginning of cycle delay 16. It is therefore apparent that the inclusion of a large period delay 16 results in limiting the accumulated transmembrane potential below the potential that would induce an action potential (below the dashed line 66). For a given active period of energy delivery, there is a characteristic delay in the waveform and electric field strength that prevents the accumulated axonal charge from reaching the threshold of evoked action potentials.

The properties of the mathematical model are selected to simulate the properties of motor neuron axons. By using this model, it was found that the benefit of cycle delay 16 to alleviate muscle contraction begins to occur at a 10ms cycle delay, and levels off at a 1 second cycle delay, as illustrated in fig. 12. This is therefore the effective range of the model that limits muscle contraction. It should be noted that these ranges will vary with respect to intensity, phase-behavior (monophasic, or biphasic, or asymmetric level changes of the biphasic), other parameters of the PEF waveform (total packet on-time, etc.), geometry of the electrode arrangement (bipolar, multipolar, or unipolar), and proximity of a given motor neuron to the PEF electrode to determine whether an action potential is ultimately evoked in the neuron. Muscle cells (skeletal muscle cells, cardiac muscle cells, smooth muscle cells) will also have similar effects and properties, affecting their susceptibility to contraction, although at different intrinsic sensitivities based on the intrinsic and specific properties of these cells.

Depending on the specifics of the PEF waveform, it is likely that the total volume of tissue treated by the PEF will begin to decrease as the cycle delay 16 increases, typically from 5ms up to and beyond 10 ms. However, the cells closest to the powered electrode will still be affected and thus treated by the tissue. Thus, although the treatment effect will vary as the cycle delay 16 begins to vary to 10 milliseconds, it is still possible to use a cycle delay that will reduce or eliminate muscle contraction to produce meaningful treatment results. Conversely, a delay as short as eliminated may be used to encourage additional muscle contraction if desired.

In some embodiments, muscle contraction may be reduced or eliminated using a delay (such as a cycle delay in the range of 5ms-100ms, preferably 10-30ms or other delay) when delivering the PEF to the solid tissue, such as when the energy delivery body 108 is positioned into the target tissue. In some embodiments, when delivering PEF to a luminal target (e.g., an airway), such as when energy delivery body 108 is positioned within a cavity of a target tissue without an electrically conductive fluid, muscle contraction may be reduced or eliminated by using a cycle delay in the range of 5ms to 100ms, preferably 10 to 30 ms. In any case, it is understood that in some embodiments, the delay is 5ms, 10ms, 25ms, 30ms, 40ms, 50ms, 60ms, 70ms, 80ms, 90ms, 100ms, in the range of 5-10ms, 10-20ms, 20-30ms, greater than 5ms, greater than 10ms, greater than 15ms, greater than 30ms, to name a few.

Temperature rise

As described herein, the delay period between the introduction and operation of the active period of the PEF waveform distributes energy deposition into the tissue over a longer period of time. This significantly affects the shape and amplitude of the temperature rise spikes characteristic of PEF therapy during pulse delivery, particularly in the region very close to the electrodes (tissue-electrode interface). This improves the safety of the treatment, reduces the chance of collateral tissue effects, and reduces the chance of discharge events (including sparks or arcing) by eliminating the possibility of hot spots in the tissue or fluid that could promote arcing. Thus, introducing a cycle delay can be used to significantly improve treatment results by attenuating the peak temperature at which the event occurs.

Referring to fig. 13, calculations of the magnitude and distribution of temperature increase from the PEF scheme can be generated by numerical simulations. In this example, three PEF regimes are compared, each regime 10 comprising a waveform 10 of a biphasic pulse 12 with a single packet 20. The first PEF scheme has no cyclic delay, the second PEF scheme includes a cyclic delay 16 of 1ms, and the third PEF scheme includes a cyclic delay 16 of 10 ms. As shown in fig. 13, a general mm scale distribution of temperatures in excess of 50 ℃ is compared between the no period delay and 1ms period delay schemes. However, the transient spike of the highest temperature at the tissue-electrode interface is significantly different. The maximum temperature produced by the no-cycle delay scheme is 175 deg.C, while the scheme with a 1ms cycle delay reaches a peak temperature of 80 deg.C, while the scheme with a 10ms cycle delay moderates the maximum temperature rise to 55 deg.C. The temperature distribution at the time of maximum temperature rise is illustrated in fig. 14A to 14B, thus reflecting different durations in the packets for 0ms delay (fig. 14A) and 1ms delay (fig. 14B). Thus, the introduction and operation of the cycle delay 16 causes a significant, scalable impact on the thermal effects occurring on the tissue.

It should be noted that these values are located at the direct tissue-electrode boundary, where the highest temperature is encountered, followed by a sharp drop in temperature. Once the pack is complete, the temperature also drops sharply. Thus, while these values indicate very high temperatures, they do not indicate that a significant degree of thermal damage can occur due to modeled PEF treatment at millimeter-scale distances from the electrode into the tissue. However, the reduced temperature spike will significantly reduce the potential for detrimental thermal damage and protein denaturation in close proximity to the electrodes and reduce the chance of a discharge event. This is two key benefits of exploiting cycle delay in these procedures.

Thus, in some embodiments, when delivering PEF therapy in blood or any electrolyte adjacent to the target tissue, such as in cardiac or vascular clinical applications, the peak temperature may be reduced using a delay (such as a cycle delay or other delay in the range of 200 μ s-20,000 μ s, preferably 500 μ s-10,000 μ s). In some embodiments, when delivering PEF to solid tissue, such as when energy delivery volumes 108 are positioned into target tissue, the peak temperature may be reduced using a delay (such as a cycle delay or other delay in the range of 200 μ β to 20,000 μ β, preferably 500 μ β to 10,000 μ β). In either case, it is understood that in some embodiments, the retardation is in the range of 500 μ s, 1000 μ s, 2000 μ s, 3000 μ s, 4000 μ s, 5000 μ s, 6000 μ s, 7000 μ s, 8000 μ s, 9000 μ s, 10,000 μ s, 200-500 μ s, 500-1000 μ s, 1000-10,000 μ s, 10,000-20,000 μ s, greater than 200 μ s, greater than 500 μ s, greater than 1000 μ s, to name a few.

In some embodiments, when delivering PEF to a luminal target (e.g., an airway), such as when energy delivery body 108 is positioned within a lumen of a target tissue without a conductive fluid, peak temperature may be reduced using a delay (such as a cycle delay or other delay in the range of 100 μ s-10,000 μ s, preferably 200 μ s-1000 μ s). In any case, it is understood that in some embodiments, the delay is in the range of 100 μ s, 200 μ s, 300 μ s, 400 μ s, 500 μ s, 600 μ s, 700 μ s, 800 μ s, 900 μ s, 1000 μ s, 100-200 μ s, 100-500 μ s, 500-1000 μ s, 1000-10,000 μ s, greater than 200 μ s, greater than 500 μ s, greater than 1000 μ s, to name a few.

Comparison of delay range to control effectiveness

In general, the susceptibility and sensitivity of a given therapy to each secondary therapeutic effect (such as gas formation, electrical discharge, cavity formation, muscle contraction and temperature rise) will vary. Table 1 below summarizes the potentially most applicable delay ranges that may be used to mitigate these effects for various target tissue classes. Notably, the table focuses on the application of mitigating secondary effects, but at other times it may be desirable to encourage these effects, so different delay ranges may be appropriate for a given therapeutic target.

TABLE 1 summary of fundamental cycle delays

Thus, the inclusion and manipulation of various delays within the PEF waveform, particularly the phase delay, period delay 16 and/or inter-packet delay 20, provides a powerful tool for significantly improving treatment results. This is achieved by eliminating or reducing the risks associated with secondary effects inherent to PEF therapy due to the nature of its delivery of high voltage electrical pulses. These effects and benefits will apply regardless of the range of energy delivered in the waveform.

Accordingly, methods for controlling the above-described secondary effects (e.g., gas formation, electrical discharge, muscle contraction, cavity formation, and temperature rise) have been provided by controlling the duration and/or sequence of constituent delays, including PEF therapy waveforms included in cycles, series, packets, beams, and/or activations, including those collectively referred to as PEF waveforms. It will be appreciated that although the examples and embodiments described herein focus on the periodic delay 16, such information (e.g., example ranges for delay values, delay positions, number of delays, delay types, etc.) applies to any delay or combination of delays in the PEF waveform. Different types of delays, alone or in combination, may have the same effect by allowing a particular therapeutic effect while dispersing energy delivery in order to mitigate various secondary effects. Thus, in some cases, the operation of the energy delivery timing may be achieved in various ways, with the same or similar results. Such effects may also be affected by the electrode arrangement.

In an effort to provide a thorough example of the various parameter combinations and resulting effects, table 2 is provided below. Table 2 provides a combination of treatment scenarios including electrode shape, circuit type, various parameter values, and treatment effect. Given a particular scenario, an example minimum of period delay 16 is provided to avoid various secondary effects (e.g., bubble formation, arcing, cavity formation). Thus, it is clear that the delay value depends on various factors related to the treatment regimen, but the unified concept is illustrated as described throughout this document.

Table 2.

The main principle of using these methods when reducing secondary effects is that the delay is too short to completely release the accumulated charge distortion and/or to recover cells and organelles from the effects induced by the pulsed electric field (e.g., cell polarization, ATP depletion, etc.). Thus, repeated exposure of target cells and tissues to subsequent pulses or series of pulses after an initial pulse or series of pulses can result in accumulation of damage to the cell, ultimately increasing its susceptibility to macromolecular transport (drugs, genetic material, etc.) or causing its death (phagocytosis, programmed cell death (dependent cell death, apoptosis, etc.), necrosis, etc.). Thus, the efficacy of PEF therapy remains consistent or at varying degrees, while secondary effects are controlled.

With respect to these approaches, secondary effects may be reduced when a delay of sufficient duration is selected, thereby attenuating or completely preventing one or more of these behaviors from being induced. This effect may also be selectively encouraged, such as by using a sufficiently low delay to encourage their occurrence, particularly when subsequent pulses within a portion of the waveform have a similar polarity arrangement. For example, in some cases, gas formation may be advantageously used by clinicians via mechanisms such as physical disruption of the treatment environment. This may be useful for purposes such as promoting cell death, promoting susceptibility of cells to cell active agents, increasing the mixing efficiency of infusions, and other potential uses. Thus, there is sometimes a need to control and encourage gas formation resulting from PEF therapy. However, for convenience, the methods described primarily herein are intended to reduce the secondary (acellular) effects that PEF therapy may produce.

Length of wave form

When introducing and/or manipulating delays in the PEF waveform, various characteristics of the waveform may change. For example, when a periodic delay 16 is introduced or added to a packet 20 of the PEF waveform 10, the time to complete one packet will increase. It will be appreciated that if the only change is an increase in delay, such an increase in packet duration or completion time will not increase the on-time of the packet. If treatment is determined by delivering a particular number of packets 20, the treatment time will increase as the packet duration increases. Likewise, if the inter-packet delay 26 is introduced or increased, the processing time will also increase if the treatment includes more than one packet.

In some cases, the PEF waveform without delay is delivered in the form of pulses or packets of length 100 μ s. When a waveform with a fundamental frequency of 400kHz is used, the waveform has 400,000 cycles per second or one cycle long by 2.5 mus. Thus, in such a case, the packet would include 40 cycles. If a period delay of 250 mus is introduced into such a packet (e.g., after each period within the packet), the length of the packet or the duration of the packet will increase by 10,000 mus, with a total duration of 10,100 mus. Table 3 below illustrates the aggregate packet time of various introduced cycle delays (e.g., 250 μ s, 500 μ s, 1000 μ s) as compared to the packet duration of a conventional PEF waveform. In this table, a cycle delay is introduced after each cycle within a packet. This behavior is the same for the phase delay instead of the period delay.

TABLE 3

In some embodiments, the inclusion of a delay may increase the packet duration to a range of approximately 1000 to 200,000 microseconds, such as 2,000. Mu.s, 5,000. Mu.s, 10,000. Mu.s, 20,000. Mu.s, 25,000. Mu.s, 30,000. Mu.s, 40,000. Mu.s, 50,000. Mu.s, 60,000. Mu.s, 70,000. Mu.s, 80,000. Mu.s, 90,000. Mu.s, 100,000. Mu.s, 110,000. Mu.s, 120,000. Mu.s, 130,000. Mu.s, 140,000. Mu.s, 150,000. Mu.s, 160,000. S, 170,000. Mu.s, 180,000. S, 190,000. Mu.s, 200,000. Mu.s, 1000-2000. Mu.s, 1000-3000. S, 1000-4000. S, 1000-5000. S, 1000-10,000. S, 10,000-20,000. S, 10,000-30,000. Mu.s, 10,000-40,000. Mu.s, 10,000-50,000. Mu.s, 50,000-200. Mu.s, 50,000-000. S, 100,000. S, 200. Mu.s, 200,000. S, 50,000. Mu.s, 200,000. Mu.s, 100,000. S, 200. S, or more than 200,000. S.

It is understood that table 3 illustrates a small sample of combinations. The waveform may include any length of delay, any number of delays, and any type of delay (i.e., without limitation, a periodic delay). The delays may be uniform (e.g., the length of the entire waveform is the same, the positions are the same) or non-uniform (e.g., at least one different length, at least one at a different position or jump position, different from packet to packet, different from batch to batch, etc.). Also, different fundamental frequencies may be used. Further, any number of packets may be present in the waveform, and any number of batches may be present, including no batches. In any case, introducing these types of delays can significantly increase packet time, as illustrated above. However, given the relatively short duration of such an increase, such an increase has little effect on the overall treatment time. In other words, the tolerable limits of treatment time during surgery far exceed such increases due to the included delays.

Delivery device and system

Typically, energy is delivered through the use of systems and devices designed for specific clinical applications. Energy may be delivered to any target within the patient's body by an adequate access route. In some embodiments, the systems and devices are designed to penetrate the body cavity into the target tissue, particularly in locations previously thought inaccessible via a percutaneous approach. Intraluminal access allows treatment of target tissue from various lumens in the body. A lumen is a space inside a tubular or hollow structure within a body and includes channels, ducts, conduits, and cavities, to name a few. Example luminal structures include blood vessels, esophagus, stomach, small and large intestines, colon, bladder, urethra, collecting ducts, uterus, vagina, fallopian tubes, ureters, kidneys, renal tubules, spinal ducts, the spine, and other organs of the body, as well as structures within and including organs such as the lungs, heart, and kidneys, to name a few. In some embodiments, the target tissue is accessed via a proximally luminal structure. In some cases, the treatment device 102 is advanced through various luminal structures or branches of luminal systems to reach a target tissue location. For example, when accessing a target tissue site via a blood vessel, the treatment device 102 may be remotely inserted and advanced through various branches of the vasculature to reach the target site. Likewise, if the luminal structure originates from a natural orifice, such as the nose, mouth, urethra, or rectum, access may be gained through the natural orifice, which in turn advances the treatment device 102 through the branches of the luminal system to reach the target tissue location. Alternatively, the luminal structure may be accessed near the target tissue via cutting or other methods. This may be the case when accessing luminal structures that are not part of a large system or are otherwise difficult to access.

The target tissue includes any luminal structure itself, tissue adjacent to such luminal structures, and any tissue accessible from such intraluminal or other methods, such as percutaneous, laparoscopic, or open surgical methods. These include cells, tissues and/or organs in the integumentary, skeletal, muscular, neural, endocrine, cardiovascular, lymphatic, respiratory, digestive, urinary and reproductive systems, to name a few. Example cells, tissues and/or organs include the luminal structure itself, systemic soft tissue located near the luminal structure, and solid organs accessible from the luminal structure, including but not limited to liver, pancreas, gall bladder, kidney, prostate, ovary, lymph nodes and lymphatic drainage tubes, underlying muscle tissue, bone tissue, brain, eye, thyroid, and the like.

Examples OF SYSTEMS that can be operated using waveforms such as those described herein include TISSUE modification SYSTEMS (e.g., ENERGY DELIVERY CATHETER SYSTEMS) described in commonly assigned patent APPLICATIONS, including international patent application No. PCT/US2017/039527 entitled "METHODs, apparatus, AND system FOR THE tree OF department" including international patent application No. PCT/US2018/067501, international patent application No. PCT/US2018/067504 entitled "OPTIMIZATION OF ENERGY DELIVERY FOR VARIOUS APPLICATIONS", international patent application No. PCT/US2020/028844 entitled "DEVICES, SYSTEMS AND METHODS FOR THE TREAT OF ABNORMAL TISSUE", international patent application No. PCT/US2020/042260 entitled "TREATIMENT OF THE REPRODUCTION TRACT WITH PULSED ELECTRICAL FILES", AND International patent application No. PCT/US2020/066205 entitled "TREATIMENT OF CARDIAC TISSUE WITH PULSED ELECTRICAL FILES", all OF which are incorporated herein by reference FOR all purposes.

Fig. 15 provides an overview illustration of an example therapy system 100 for delivering specialized PEF energy. In this embodiment, the system 100 includes an elongated device 102, the elongated device 102 including a shaft 106 having a distal end 103 and a proximal end 107. Device 102 includes an energy delivery body 108, energy delivery body 108 being generally illustrated as a dashed circle near distal end 103 of shaft 106. It is to be understood that the energy delivery body 108 may take a variety of forms with structural differences that prevent the rendering of a single representation, but various example embodiments will be described and illustrated herein. Energy delivery body 108 may be mounted on the exterior of shaft 106 or integral with the exterior of shaft 106 so as to be visible from the outside. Alternatively, energy delivery body 108 may be contained within shaft 106 and exposed by advancing or retracting shaft 106 itself from shaft 106. Likewise, there may be more than one energy delivery body 108 and more than one energy delivery body 108 may be external, internal, or both. In some embodiments, shaft 106 is composed of a polymer, such as an extruded polymer. It will be appreciated that in some embodiments, shaft 106 is constructed of multiple layers of materials having different hardnesses to control flexibility and/or stiffness. In some embodiments, shaft 106 is reinforced with various elements such as individual wires or a braid of wires. In either case, such filaments may be flat filaments or round filaments. The wire braid has a braid pattern, and in some embodiments, the braid pattern is tailored for a desired flexibility and/or stiffness. In other embodiments, the wire braid reinforcing the shaft 106 may be advantageously combined with multiple layers of materials having different stiffness to provide additional control of flexibility and/or stiffness along the length of the shaft.

In any case, each energy delivery body 108 includes at least one electrode for delivering PEF energy. Typically, energy delivery body 108 comprises a single delivery electrode and operates in a monopolar arrangement by providing energy between energy delivery body 108 disposed near distal end 103 of device 102 and return electrode 140 located on the skin of the patient. However, it will be understood that bipolar energy delivery and other arrangements may alternatively be used. When bipolar energy delivery is used, the device 102 may include multiple energy delivery bodies 108, the energy delivery bodies 108 configured to operate in a bipolar manner, or may include a single energy delivery body 108 having multiple electrodes configured to operate in a bipolar manner. The device 102 generally includes a handle 110 disposed near the proximal end 107. Handle 110 is used to manipulate device 102 and generally includes actuator 132 for operating energy delivery body 108. In some embodiments, energy delivery body 108 transitions from a closed or retracted position (during entry) to an open or exposed position (for energy delivery), which is controlled by actuator 132. Thus, the actuator 132 typically has the form of a knob, button, lever, slider, or other mechanism. It will be appreciated that in some embodiments, the handle 110 includes a port 111 for introducing a liquid, agent, substance, tool, or other device to be delivered through the device 102. Exemplary liquids include suspensions, mixtures, chemicals, fluids, chemotherapeutic agents, immunotherapeutic agents, micelles, liposomes, embolic agents, nanoparticles, drug eluting particles, genes, plasmids, and proteins, to name a few.

The device 102 is in electrical communication with a generator 104 configured to generate PEF energy. In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage/retrieval unit 156 (e.g., memory and/or database), and an energy storage subsystem 158 that generates and stores energy to be delivered. In some embodiments, a user interface 150 on the generator 104 is used to select a desired treatment algorithm 152. In other embodiments, the algorithm 152 is automatically selected by the generator 104 based on information obtained by one or more sensors, as will be described in more detail in later sections. Various energy delivery algorithms may be used. In some embodiments, one or more capacitors are used for energy storage/delivery, but any other suitable energy storage element may be used. In addition, one or more communication ports are typically included.

As illustrated in fig. 15, the distal end 103 of the device 102 is generally advanceable through a delivery device, such as the endoscope 10. The endoscope 10 generally includes a control body 12 attached to an elongated insertion tube 14, the elongated insertion tube 14 having a distal tip 16. The endoscope 10 has an internal lumen accessible through the port 18, and the distal end 103 of the device 102 is threaded into the port 18. Shaft 106 of device 102 can be advanced through the internal lumen and out distal tip 16. Imaging is accomplished through the endoscope 10 using a light guide tube 20 having an endoscope connector 22 connected to light and energy sources. The distal tip 16 of the endoscope may be equipped with visualization techniques including, but not limited to, video, ultrasound, laser scanning, and the like. These visualization techniques collect signals consistent with their design and transmit them to a video processing unit, either through the length of the shaft over the wire or wirelessly. The video processing unit then processes the video signal and displays the output on a screen. It will be appreciated that endoscope 10 is generally specific to the anatomical location in which it is used, such as gastroscopes (upper gastrointestinal endoscopy including the stomach, esophagus, and small intestine (duodenum)), colonoscopes (large intestine), bronchoscopes (lung), laryngoscopes (larynx), cystoscopes (urinary tract), duodenoscopes (small intestine), enteroscopes (digestive system), ureteroscopes (ureter), hysteroscopes (cervix, uterus), and the like. It will be appreciated that in other embodiments, the device 102 may be delivered through a catheter, sheath, introducer, needle, or other delivery system.

Once within the lumen, the target tissue region is accessed, energy can be delivered to the target tissue in a variety of ways. In one arrangement, the energy delivery body 108 is positioned within the body lumen and energy is delivered to the target tissue, the energy having entered the body lumen, passed through at least a portion of the lumen wall to tissue within and/or at least partially surrounding the lumen wall, or passed through the body lumen arm to the target tissue within and adjacent to the lumen arm. In another arrangement, energy delivery body 108 is advanced through the lumen wall and inserted within or adjacent to the target tissue outside of the lumen wall. It will be appreciated that such arrangements may be combined, involving at least two energy delivery bodies 108, one positioned within the body lumen and one extending through the body lumen wall. In some embodiments, each energy delivery body 108 functions in a monopolar fashion (e.g., with a remotely placed return electrode). In other embodiments, at least some of energy delivery bodies 108 function in a bipolar manner (e.g., using energy delivery bodies 108 as return electrodes). Alternatively, each of the two energy delivery bodies 108 may be positioned on opposite sides of the lumen wall and function in a bipolar manner to treat tissue therebetween (e.g., within the lumen wall). These delivery options are possible because the lumen itself is preserved throughout the treatment process, and allow for treatment of tissue within, on, or near the lumen itself. Such therapy delivery allows access to previously inaccessible tissue, such as tumors or diseased tissue that has invaded the lumen wall or at least partially wrapped around the body lumen, which are too close to be surgically removed or treated with conventional focused therapy. Many conventional focal therapies, such as thermal energy therapy, can damage or destroy the structure of the lumen wall due to thermal protein coagulation and the like.

Endoscopic methods are also suitable for monopolar energy delivery. As mentioned, monopolar delivery involves passage of current from the energy delivery body 108 (near the distal end of the device 102) to the target tissue and through the patient to a return pad 140 positioned against the patient's skin to complete the current circuit. Thus, in some embodiments, device 102 includes only one energy delivery body 108 or electrode. This allows the device 102 to have a low profile so as to be positionable in smaller body cavities. This also allows deep penetration of the tissue surrounding energy delivery vehicle 108. Also, when penetrating the lumen wall with such devices, only one penetration is required for each treatment, as only one energy delivery body 108 is used. It will be appreciated that additional penetration may occur due to various device designs or treatment protocols, but in some embodiments, the monopolar delivery design reduces the invasiveness of the procedure, simplifies the device and treatment design, and provides a superior treatment zone in the target tissue.

In contrast, bipolar delivery involves passing current through the target tissue between two electrodes on the same energy delivery body 108, on different energy delivery bodies 108, or with other arrangements. Most conventional energy therapies are bipolar and usually percutaneous. Such treatments involve multiple penetrations of the skin, thereby increasing discomfort, prolonging healing time and increasing the complexity of the procedure. It will be appreciated that while the systems described herein can be utilized in a variety of forms, including bipolar and percutaneous arrangements, the device features will generally be combined in a manner that reduces overall invasiveness and provides better results.

Fig. 16 illustrates another embodiment of a treatment device 102 configured to deliver specialized PEF energy, particularly configured to deliver focused therapy. In this embodiment, the device 102 includes an elongate shaft 106 having at least one energy delivery body 108 near its distal end 103 and a handle 110 near its proximal end 107. In this embodiment, at least one energy delivery body 108 includes a cylindrically shaped "focusing electrode". The cylindrical shape has a rounded, substantially flat surface or a curved surface for positioning against tissue. In some embodiments, the device 102 has a total length of 50-150cm, preferably 100-125cm, more preferably 110-115cm. Also, in some embodiments, the device has an outer diameter of 3-15Fr, preferably 4-12Fr, more preferably 7-8.5Fr, of 7 Fr. It will be appreciated that in some embodiments, shaft 106 has deflectable end 121, and optionally deflectable end 121 may have a length of 50-105mm, thereby creating a curve having a diameter in the range of about 15-55 mm. The deflection may be accomplished by a variety of mechanisms including a pull wire extending to the handle 110. Thus, the handle 110 is used to operate the device 102, particularly to manipulate the distal end 103 during delivery and treatment. Via a cable 13 connectable to the generator 104, energy is provided to the device 102 and thus to the at least one energy delivery body 108.

In some embodiments, the treatment device 102 of fig. 16 is used to treat cardiac tissue, particularly to treat cardiac arrhythmias, such as atrial fibrillation. Fig. 17 illustrates a portion of a heart H showing a cutaway view of the right atrium RA and the left atrium LA. The largest pulmonary veins are the four major pulmonary veins (right superior pulmonary vein RSPV, right inferior pulmonary vein RIPV, left superior pulmonary vein LSPV, and left inferior pulmonary vein LIPV), with two on each lobe leading to the left atrium LA of the heart H. In some embodiments, treatment of atrial fibrillation involves positioning the treatment device 102 deep in the pulmonary veins and gradually withdrawing back to the ostium proximal to the mapping catheter. Mapping and treatment is then initiated.

In some embodiments, the tissue surrounding the ostium of the lower pulmonary vein LIPV is treated in a point-by-point manner by using the treatment device 102 (with the aid of mapping) to form a circular treatment band around the left lower pulmonary vein LIPV, as illustrated in fig. 18. In some cases, dedicated navigation software may be used to allow for proper positioning of the treatment catheter 120. Delivery electrode 122 is positioned near or against the target tissue region and provides energy to delivery electrode 122 to create treatment zone a. Since the energy is delivered to a localized area (focused delivery), the electrical energy is concentrated over a smaller surface area, resulting in a stronger effect than delivered by electrodes extending circumferentially around the lumen or aperture. This also forces the electrical energy to be delivered in a phased regional approach, mitigating the potential effects of preferential current pathways through surrounding tissue. These preferential current paths are regions having electrical characteristics that induce a locally increased current flow therethrough rather than through adjacent regions. Such pathways may result in an irregular current distribution around the circumference of the target lumen, which may distort the electric field and cause an irregular increase in the treatment effect in some areas and a decrease in the treatment effect in other areas. This can be mitigated or avoided by using focused therapy, which can stabilize the therapeutic effect around the circumference of the target region. Thus, by energizing certain regions at once, the electrical energy is "forced" across different regions of the circumference, thereby ensuring an improved degree of circumferential regularity of the treatment. Fig. 18 illustrates the repeated application of energy in a point-by-point fashion around the left inferior pulmonary vein LIPV using the treatment device 102 to create a circular treatment zone. As illustrated, each treatment zone a overlaps with an adjacent treatment zone a in this embodiment to create a continuous treatment zone. The size and depth of each treatment zone a may depend on a variety of factors, such as parameter values, treatment time, tissue characteristics, and the like. It will be appreciated that the number of treatment zones a may vary depending on various factors, particularly the unique condition of the anatomy and electrophysiology of each patient. In some embodiments, the number of treatment zones a includes one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty-five, thirty, or more.

When all electrical connections between the atrium and the veins are treated, there is electrical silencing in the pulmonary veins, where only far-field atrial signals are recorded. Occasionally, a spike in electrical activity is seen in the pulmonary veins, not being conducted to the rest of the atria; these clearly show electrical discontinuities from the veins of the rest of the atrial muscle.

It is to be understood that in various embodiments, the treatment device 102 includes various specialized features. For example, in some embodiments, the device 102 includes a mechanism for measuring in real time the contact force applied by the catheter tip to the patient's heart wall during an ablation procedure. In some embodiments, the mechanism is included in the shaft 120 and includes a three-axis optical force sensor using white light interferometry. By monitoring and improving the applied force throughout the procedure, the user is able to better control the device 102, thereby creating a more consistent and effective lesion.

Referring back to fig. 16, in some embodiments, device 102 includes one or more additional electrodes 109 (e.g., ring electrodes) positioned along shaft 120 proximal to energy delivery body 108. In some embodiments, some or all of the electrodes 109 may be used for stimulation and recording (for electrophysiology mapping), thus eliminating the need for a separate cardiac mapping catheter when ablating using the device 102.

In some embodiments, the device 102 includes a thermocouple temperature sensor, optionally embedded in the energy delivery body 108. Similarly, in some embodiments, the device 102 includes a lumen that can be used for irrigation and/or aspiration. In some embodiments, the device 102 includes one or more sensors that can be used to determine temperature, impedance, resistance, capacitance, conductivity, and/or permittivity, to name a few. In some embodiments, one or more electrodes function as one or more sensors. In other embodiments, one or more sensors are separate from the electrodes. The sensor data may be used to plan therapy, monitor therapy, and/or provide direct feedback via a processor 154, which processor 154 may in turn alter the energy delivery algorithm 152. For example, impedance measurements can be used to determine not only the initial dose to be applied, but also whether further treatment is required.

It will be appreciated that in some embodiments, the system 100 includes an automated therapy delivery algorithm that dynamically responds to inputs such as temperature, impedance at various voltages or AC frequencies, therapy duration or other timing aspects of the energy delivery pulses, therapy power and/or system state, and adjusts and/or terminates therapy.

As previously mentioned, one or more energy delivery algorithms 152 may be programmable or may be preprogrammed into the generator 104 for delivery to the patient P. One or more energy delivery algorithms 152 specify electrical signals that provide energy delivered to the heart wall that is non-thermal (e.g., below a threshold for thermal ablation; below a threshold for inducing coagulative thermal injury), thereby reducing or avoiding inflammation, and/or preventing matrix protein denaturation in luminal structures. Generally, the algorithm 152 is customized to affect tissue to a predetermined depth and/or volume and/or to target a particular type of cellular response to the energy delivered.

Fig. 19A illustrates another embodiment of a therapeutic energy delivery catheter or device 102. In this embodiment, the device 102 has an elongate shaft 106, the elongate shaft 106 having at least one energy delivery body 108 near its distal end and a handle 110 at its proximal end. The device 102 may be connected to the generator 104 as part of the treatment system 100. Among other features, the connection of the device 102 to the generator 104 provides electrical energy to the energy delivery body 108. In this embodiment, energy delivery body 108 includes a plurality of filaments or ribbons 120 constrained by proximal constraint 122 and distal constraint 124 and forming a spiral basket that functions as an electrode. In an alternative embodiment, the wire or ribbon is straight rather than forming a spiral shape (i.e., configured as a straight basket). In yet another embodiment, energy delivery body 108 is laser cut from a tube. It will be appreciated that various other designs may be used. For example, fig. 19B illustrates an energy delivery body 108 having a paddle shape. In this embodiment, energy delivery body 108 is comprised of a plurality of wires or ribbons 120, the plurality of wires or ribbons 120 arranged to form a flat pad or paddle. Such an energy delivery body 108 is flexible so as to be retracted into the shaft 106. Referring back to fig. 19A, in this embodiment, the energy delivery body 108 is self-expandable and is delivered to the target area in a collapsed configuration. This collapsed configuration may be achieved, for example, by a sheath 126 placed over the energy delivery body 108. The instrument shaft 106 (within the sheath 126) terminates in a proximal constraint 122, leaving a distal constraint 124 substantially axially unconstrained and free to move relative to the shaft 106 of the device 102. Advancing sheath 126 over energy delivery body 108 allows distal constraining member 124 to move forward, thereby lengthening/collapsing and constraining energy delivery body 108.

As shown in this example, the device 102 includes a handle 110 at its proximal end. In some embodiments, the handle 110 is removable, such as by depressing the handle removal button 130. In this embodiment, handle 110 includes an energy delivery body operating knob or actuator 132, wherein movement of actuator 132 causes expansion or retraction/collapse of the basket electrode. In this example, the handle 110 also includes a work port clasp 134 for optional connection with an endoscope or other type of visualization device and a cable insertion port 136 for connection with the generator 104. It will be appreciated that various types of visualization may be used, including angiography (optionally including markers), computed tomography, optical coherence tomography, ultrasound, and direct video visualization, to name a few.

In this embodiment, therapeutic energy delivery device 102 may be connected to generator 104 and to a dispersive (return) electrode 140 applied externally to the skin of patient P. Thus, in this embodiment, monopolar energy delivery is achieved by providing energy between energy delivery body 108 disposed near the distal end of device 102 and return electrode 140. However, it will be understood that bipolar energy delivery and other arrangements may alternatively be used. When bipolar energy delivery is used, the overall design of therapeutic energy delivery device 102 may be different, such as to include multiple energy delivery bodies 108, or may look similar in overall design, such as to include a single energy delivery body 108 configured to operate in a bipolar manner. In some cases, bipolar energy delivery allows for the use of lower voltages to achieve therapeutic effects as compared to monopolar energy delivery. In a bipolar configuration, the positive and negative electrodes are close enough to provide a therapeutic effect at and between the electrode poles. This can extend the therapeutic effect over a larger, shallower surface area than a monopole, and therefore requires a lower voltage to obtain the therapeutic effect. Also, this lower voltage can be used to reduce the penetration depth.

As previously mentioned, one or more energy delivery algorithms 152 may be programmable or may be preprogrammed into the generator 104 for delivery to the patient. One or more energy delivery algorithms 152 specify electrical signals that provide energy delivered to non-thermal (e.g., below a threshold for thermal ablation; below a threshold for inducing coagulation thermal damage) tissue, thereby reducing or avoiding inflammation, and/or preventing matrix protein denaturation in luminal structures. Typically, the algorithm 152 is customized to affect the tissue to a predetermined depth and/or target a particular type of cellular response to the energy delivered. It will be appreciated that the depth and/or targeting may be influenced by the parameters of the energy signal specified by the one or more energy delivery algorithms 152, the design of the device 102 (and in particular the one or more energy delivery bodies 108), and/or the selection of monopolar or bipolar energy delivery. Typically, the depth is up to 0.01cm, up to 0.02cm, 0.01-0.02cm, up to 0.03cm, 0.03-0.05cm, up to 0.08cm, up to 0.09cm, up to 0.1cm, up to 0.2cm, up to 0.5cm, up to 0.7cm, up to 1.0cm, up to 1.5cm, up to 2.0cm, up to 2.5cm, up to 3.0cm, up to 3.5cm, up to 4.0cm, up to 4.5cm, or up to 5.0cm, to name a few. These depths may be greater for circumferential focal targets, or they may exist throughout the circumferential depth through the lumen and parenchymal tissue.

Fig. 20A-20B illustrate another embodiment of a treatment system 100. Here, the system 100 is configured to treat target tissue located at least partially outside the body lumen, where the treatment may benefit from treating energy originating at a distance from the body lumen. In this embodiment, the system 100 includes an energy delivery device 102 that is connectable to a generator 104. It will be appreciated that many of the system components described above, such as certain aspects of the device 102, generator 104, and other accessories, are used in this embodiment of the system 100. Accordingly, such descriptions provided above apply to the system 100 described below. The primary difference is with respect to the energy delivery body 108.

Here, device 102 includes a shaft 106, the shaft 106 having a distal end 103, a proximal end 107, and at least one lumen 105 extending at least partially therethrough. Likewise, device 102 also includes at least one energy delivery body 108. In this embodiment, energy delivery body 108 has the form of a stylet 500, stylet 500 being disposed within lumen 105 of shaft 106. The probe 500 has a probe tip 502 that can be advanced through the lumen 105 and can extend from the distal end 103 of the shaft 106 (extending in fig. 20A to show detail). In this embodiment, the tip 502 has a pointed shape configured to penetrate tissue, such as similar to a needle. Thus, in this embodiment, the probe tip 502 is used to penetrate the lumen wall W and surrounding tissue so that it can be inserted into the target tissue outside the body lumen. Thus, the probe 500 is flexible enough for endoluminal delivery, yet has sufficient column strength to penetrate the lumen wall W and the target tissue. In some embodiments, the device 102 has markings to indicate to the user the distance the probe tip 502 has been advanced in order to ensure the desired placement.

In some embodiments, the probe extends less than about 0.5cm, 1cm, 2cm, 3cm, 4cm, 5cm, 6cm, 7cm, 8cm, or greater than 8cm from the distal end 103 of the shaft 106. In some embodiments, the probe extends 1-3cm or 2-3cm from the distal end of shaft 106. In some embodiments, the probe is No. 18, no. 19, no. 20, no. 21, no. 22, no. 23, no. 24, or No. 25. In some embodiments, the probe 500 is constructed of a conductive material, thereby acting as an electrode. Therefore, the electrode should have the size of the exposed probe. Example materials include stainless steel, nitinol, cobalt chromium alloy, copper and gold. Thus, in these embodiments, PEF energy may be transmitted through probe 500 to probe tip 502. Thus, the shaft 106 is constructed of an insulating material or covered by an insulating sheath. Example insulating materials include polyimide, silicone, polytetrafluoroethylene, and polyether block amide. The insulating material may be uniform or vary along the length of the shaft 106 or sheath. Also, in either case, the insulating material typically comprises complete electrical insulation. However, in some embodiments, the insulating material allows some leakage current to penetrate.

When the probe 500 is energized, the insulated shaft 106 protects surrounding tissue from the therapeutic energy and directs the energy to the probe tip 502 (and any exposed portions of the probe 500), which probe tip 502 is capable of delivering the therapeutic energy to the surrounding tissue. Thus, the tip 502 acts as a delivery electrode and its size can be selected based on the amount of probe 500 exposed. Larger electrodes may be formed by exposing a larger number of probes 500, while smaller electrodes may be formed by exposing a smaller number of probes 500. In some embodiments, the exposed tip 502 (measured from its distal end to the distal edge of the insulated shaft) has a length of 0.1cm, 0.2cm, 0.3cm, 0.4cm, 0.5cm, 0.6cm, 0.7cm, 0.8cm, 0.9cm, 1cm, 2cm, 3cm, greater than 3cm, up to 8cm, less than or equal to 0.1cm, less than or equal to 0.3cm, less than or equal to 0.5cm, less than or equal to 1cm, 0.2-0.3cm, 0.1-0.5cm, 0.1-1cm, and all ranges and subranges therebetween, during energy delivery. In addition to changing the size of the electrode, the tip 502 may be retracted into the shaft 106 to allow for atraumatic endoscopic delivery, and may then be advanced to the target tissue as desired. In this embodiment, advancement and retraction is controlled by an actuator 132 (e.g., a knob, button, lever, slider, or other mechanism) on the handle 110 attached to the proximal end 107 of the shaft 106. It will be appreciated that the shaft 106 itself may be advanced toward the target tissue, whether or not the probe 103 is advanced from the distal end of the shaft 106. In some embodiments, the distal end of the shaft 106 is advanced up to 20cm into the tissue, such as from the outer surface of the luminal structure or from the outer surface of the patient's body.

The handle 110 is connected to the generator 104 using a dedicated power plug 510. The energy plug 510 has a first end 512 connected to the handle 110 and a second end 514 connected to the generator 104. The connection of the first end 512 to the handle 110 is expanded in detail in fig. 20B. In this embodiment, the first end 512 has an adapter 516, the adapter 516 including a connection wire 518 extending therefrom. The connecting wire 518 may be inserted into the proximal end of the probe 500 within the handle 110. This allows energy to be transferred from the generator 104 to the probe 500 through the connecting wire 518. Thus, the probe 500 can be charged over its entire length, but due to the presence of the insulated shaft 106, only the exposed tip 502 delivers energy to the tissue.

The devices, systems, and methods described herein may be used alone or in combination with other treatments. Such combination therapy is particularly useful for cancer therapy. For example, the PEF treatments described herein can be used in combination with a variety of non-surgical therapies, neoadjuvant and adjuvant therapies, such as radiation therapy, chemotherapy, targeted therapy/immunotherapy, focused therapy, gene therapy, plasmid therapy, and the like. Exemplary focused therapies include microwave ablation, radio frequency ablation, cryoablation, high Intensity Focused Ultrasound (HIFU), and other pulsed electric field ablation therapies. Such combinations may modulate the tissue to bring about improved responsiveness, and in some cases greater than the synergistic response of either therapy alone. In addition, due to the nature of the treatment, PEF treatment as described herein may elicit an ectopic effect.

Energy algorithm

The PEF energy is provided by one or more energy delivery algorithms 152. In some embodiments, algorithm 152 specifies a signal having a waveform that includes a series of energy packets, where each energy packet includes a series of high voltage pulses. In such embodiments, the algorithm 152 specifies parameters of the signal, such as energy amplitude (e.g., voltage) and duration of applied energy, including the number of packets, the number of pulses within a packet, and the fundamental frequency of the pulse sequence, to name a few. Additional parameters may include switching time or inter-phase delay between polarities in a biphasic pulse, dead time or period delay between biphasic periods, and rest time or inter-packet delay between packets. In some embodiments, there is a fixed rest time between packets, while in other embodiments, the packets are cardiac cycle gated and thus vary with the heart rate of the patient. There may be intentionally varying rest period algorithms or no rest periods may be applied between packets. Feedback loops based on sensor information and auto-close specifications and/or the like may be included.

Fig. 21A illustrates an embodiment of a waveform 400 of a signal specified by the energy delivery algorithm 152. Here, two packets are shown, a first packet 402 and a second packet 404, where the packets 402, 404 are separated by an inter-packet delay or rest period 406. In this embodiment, each packet 402, 404 consists of a first biphasic period (comprising a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic period (comprising a second positive pulse peak 408 'and a second negative pulse peak 410'). The first and second biphasic pulses are separated by a period delay or dead time 412 (i.e., pause) between each pulse. In this embodiment, the biphasic pulse is symmetrical so that the set voltage 416 is the same for both positive and negative peaks. Here, the biphasic symmetrical wave is also a square wave, so that the amplitude and time of the positive voltage wave is approximately equal to the amplitude and time of the negative voltage wave.

A. Voltage of

The voltage used and considered may be the top of a square wave, may be a peak in a sinusoidal or sawtooth waveform, or may be the RMS voltage of a sinusoidal or sawtooth waveform. In some embodiments, the energy is delivered in a monopolar fashion and each high voltage pulse or set voltage 416 is between about 500V to 10,000v, specifically between about 3500V to 4000V, about 3500V to 5000V, about 3500V to 6000V, including all values and subranges between about 250V, 500V, 1000V, 1500V, 2000V, 2500V, 3000V, 3500V, 4000V, 4500V, 5000V, 5500V, 6000V, to name a few. The voltage delivered to the tissue may be based on a set point on the generator 104 while accounting for electrical losses along the length of the device 102 due to the inherent impedance of the device 102, or the losses along the length may not be accounted for, i.e., the delivered voltage may be measured at the generator or instrument tip.

It will be appreciated that the set voltage 416 may vary depending on whether the energy is delivered in a monopolar or bipolar manner. In bipolar delivery, lower voltages can be used because the electric field is smaller and more directional. The bipolar voltage selected for therapy depends on the separation distance of the electrodes, while a monopolar electrode configuration using one or more remote discrete pad electrodes may be delivered with less consideration to the exact placement of the catheter and discrete electrodes placed on the body. In monopolar electrode embodiments, larger voltages are typically used due to the dispersive behavior of the delivered energy through the body to dispersive electrodes on the order of 10cm to 100cm of effective separation distance. In contrast, in a bipolar electrode configuration, the relatively close active area of the electrodes on the order of 0.5mm to 10cm (including 1mm to 1 cm) results in a greater impact on the concentration of electrical energy and the effective dose delivered to the tissue from the separation distance. For example, if the target voltage to distance ratio is 3000V/cm to evoke the desired clinical effect at the appropriate tissue depth (1.3 mm), such as a separation distance change from 1mm to 1.2mm, this would result in the need to increase the treatment voltage from 300V to about 360V, a 20% change.

B. Frequency of

It will be appreciated that when the signal is continuous, the number of biphasic cycles per second is the frequency. In some embodiments, biphasic pulses are used to reduce undesirable muscle stimulation, particularly myocardial stimulation. In other embodiments, the pulse waveform is monophasic and has no definite natural frequency. Instead, the fundamental frequency can be considered by doubling the monophasic pulse length to derive the frequency. In some embodiments, the frequency of the signal is in the range of 100kHz to 1MHz, more specifically 100kHz to 1000kHz. In some embodiments, the frequency of the signal is in the range of about 100-600kHz, which typically penetrates the lumen wall in order to treat or affect specific cells located somewhat deeply, such as submucosal cells or smooth muscle cells. In some embodiments, the fundamental or fundamental frequency of the signal is in the range of about 600kHz-1000kHz or 600kHz-1MHz, which frequency typically penetrates the lumen wall in order to treat or affect certain cells that are somewhat superficial, such as epithelial or endothelial cells. It is understood that at some voltages, frequencies at or below 100-250kHz may cause undesirable muscle stimulation. Thus, in some embodiments, the frequency of the signal is in the range of 400-800kHz or 500-800kHz, such as 500kHz, 550kHz, 600kHz, 650kHz, 700kHz, 750kHz, 800kHz. In particular, in some embodiments, the frequency of the signal is 600kHz. Furthermore, cardiac synchronization is often used to reduce or avoid undesirable myocardial stimulation during periods of sensitive rhythm. It will be appreciated that higher frequencies may be used with components that minimize signal artifacts.

C. Voltage-frequency balancing

The frequency of the delivered waveform can be varied synchronously with respect to the treatment voltage to maintain adequate treatment effect. Such simultaneous changes should include a reduction in frequency that causes a stronger effect, along with a reduction in voltage that causes a weaker effect. For example, in some cases, 3000V may be used to deliver therapy in a monopolar fashion with a waveform frequency of 800kHz, while in other cases 2000V may be used to deliver therapy with a waveform frequency of 400 kHz.

When used in the opposite direction, the treatment parameters may operate in an overly effective manner, which may increase the likelihood of muscle contraction or the risk effect on undesirable tissue (such as cartilage in airway treatment). For example, if the frequency is increased and the voltage is decreased, such as 2000V at 800kHz, the treatment may not have sufficient clinical therapeutic benefit. Conversely, if the voltage is increased to 3000V and the frequency is decreased to 400kHz, there may be an undesirable extension of the therapeutic effect on side-sensitive tissue. In some cases, over-treatment of these undesirable tissues may lead to morbidity or safety issues for the patient, such as destruction of cartilage tissue in the airways sufficient to cause airway collapse, or destruction of smooth muscle in the gastrointestinal tract sufficient to cause disruption of normal peristalsis. In other cases, over-treatment of non-target or undesirable tissue may have benign clinical consequences and if it is over-treated will not affect patient response or morbidity.

D. Bag (CN)

As mentioned, the algorithm 152 specifies a signal having a waveform that includes a series of energy packets, where each energy packet includes a series of high voltage pulses. The period count 420 is one-half the number of pulses in each bi-phase. Referring to fig. 21A, the first packet 402 has two cycle counts 420 (i.e., four biphasic pulses). In some embodiments, cycle count 420 is set to between 1 and 100 per packet, including all values and subranges therebetween. In some embodiments, cycle count 420 is up to 5 pulses, up to 10 pulses, up to 25 pulses, up to 40 pulses, up to 60 pulses, up to 80 pulses, up to 100 pulses, up to 1,000 pulses, or up to 2,000 pulses, including all values and subranges therebetween.

The packet duration is determined by the cycle count, in addition to factors such as insertion delay. In some embodiments, the packet duration is in the range of about 50 to 1000 microseconds, such as 50 μ s, 60 μ s, 70 μ s, 80 μ s, 90 μ s, 100 μ s, 125 μ s, 150 μ s, 175 μ s, 200 μ s, 250 μ s, 100 to 250 μ s, 150 to 250 μ s, 200 to 250 μ s, 500 to 1000 μ s, to name a few. In other embodiments, the packet duration is in the range of approximately 100 to 1000 microseconds, such as 150 μ s, 200 μ s, 250 μ s, 500 μ s, or 1000 μ s. <xnotran> , 1000 200,000 , 2,000 μ s, 5,000 μ s, 10,000 μ s, 20,000 μ s, 25,000 μ s, 30,000 μ s, 40,000 μ s, 50,000 μ s, 60,000 μ s, 70,000 μ s, 80,000 μ s, 90,000 μ s, 100,000 μ s, 110,000 μ s, 120,000 μ s, 130,000 μ s, 140,000 μ s, 150,000 μ s, 160,000 μ s, 170,000 μ s, 180,000 μ s, 190,000 μ s, 200,000 μ s, 1000-2000 μ s, 1000-3000 μ s, 1000-4000 μ s, 1000-5000 μ s, 1000-10,000 μ s, 10,000-20,000 μ s, 10,000-30,000 μ s, 10,000-40,000 μ s, 10,000-50,000 μ s, 50,000-100,000 μ s, 50,000-150,000 μ s, 50,000-200,000 μ s, 10,000 μ s, 25,000 μ s, 50,000 μ s, 100,000 μ s, 200,000 μ s, . </xnotran>

E. Wave form

Fig. 21A illustrates an embodiment of a waveform 400 having symmetrical pulses such that the voltage and duration of the pulses in one direction (i.e., positive or negative) are equal to the voltage and duration of the pulses in the other direction. Fig. 21B illustrates an example waveform 400 specified by another energy delivery algorithm 152, where the waveform 400 has a voltage imbalance. Here, two packets are shown, a first packet 402 and a second packet 404, wherein the packets 402, 404 are separated by a rest period 406. In this embodiment, each packet 402, 404 includes a first two-phase period (including a first positive pulse peak 408 having a first voltage V1 and a first negative pulse peak 410 having a second voltage V2) and a second two-phase period (including a second positive pulse peak 408 'having a first voltage V1 and a second negative pulse peak 410' having a second voltage V2). The first voltage V1 is here greater than the second voltage V2. The first two-phase period and the second two-phase period are separated by a dead time 412 between each pulse. Thus, the voltage in one direction (i.e., positive or negative) is greater than the voltage in the other direction, so that the area under the positive portion of the curve is not equal to the area under the negative portion of the curve. This unbalanced waveform may lead to more pronounced therapeutic effects because the dominant positive or negative amplitude results in longer durations of the same charged cell membrane charge potential. In this embodiment, the first positive peak 408 has a set voltage 416 (V1) that is greater than the set voltage 416' (V2) of the first negative peak 410. Fig. 21C illustrates a further example of waveforms having unequal voltages. Here, four different types of packets are shown in a single chart for centralized illustration. The first packet 402 is composed of pulses with unequal voltages but equal pulse widths, with no phase-to-phase delay and no dead time. Thus, the first packet 402 consists of four biphasic pulses, each of which comprises a positive peak 408 having a first voltage V1 and a negative peak 410 having a second voltage V2. The first voltage V1 is here greater than the second voltage V2. The second packet 404 consists of pulses with unequal voltages but symmetrical pulse widths (as in the first pulse 402), with an inter-phase delay equal to the cycle delay. The third packet 405 consists of pulses with unequal voltages but symmetrical pulse widths (as in the first pulse 402), where the inter-phase delay is shorter than the cycle delay. The fourth packet 407 consists of pulses with unequal voltages but symmetrical pulse widths (as in the first pulse 402), where the phase-to-phase delay is greater than the cycle delay. It will be appreciated that in some embodiments, the positive and negative phases of the biphasic waveform are not the same, but are balanced, with the voltage in one direction (i.e., positive or negative) being greater than the voltage in the other direction, but the pulse length is calculated so that the area under the positive phase curve is equal to the area under the negative phase curve.

In some embodiments, the imbalance includes pulses having pulse widths of unequal duration. In some embodiments, the biphasic waveform is unbalanced such that the voltage in one direction is equal to the voltage in the other direction, but the duration (i.e., positive or negative) of one direction is greater than the duration of the other direction, such that the area under the curve of the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

Fig. 21D illustrates a further example of waveforms having unequal pulse widths. Here, four different types of packets are shown in a single chart for a centralized description. The first packet 402 consists of pulses with equal voltages but unequal pulse widths, with no phase and period delays. Thus, the first packet 402 consists of four biphasic pulses, each biphasic pulse comprising a positive peak 408 having a first pulse width PW1 and a negative peak 410 having a second pulse width PW2. Here, the first pulse width PW1 is greater than the second pulse width PW2. The second packet 404 consists of pulses with equal voltages but unequal pulse widths (as in the first pulse 402), with an inter-phase delay equal to the cycle delay. The third packet 405 consists of pulses of equal voltage but unequal pulse width (as in the first pulse 402), with shorter inter-phase delays than the cycle delay. The fourth packet 407 is composed of pulses of equal voltage but unequal pulse width (as in the first pulse 402), with an inter-phase delay greater than the cycle delay.

Fig. 21E illustrates an example waveform 400 specified by another energy delivery algorithm 152, where the waveform is monophasic, which is a special case of imbalance where there is only a positive portion of the waveform or only a negative portion of the waveform. Here, two packets are shown, a first packet 402 and a second packet 404, where the packets 402, 404 are separated by an inter-packet delay or rest period 406. In this embodiment, each packet 402, 404 consists of a first monophasic pulse 430 and a second monophasic pulse 432. The first monophasic pulse 430 and the second monophasic pulse 432 are separated by a period delay or dead time 412 between each cycle. Such monophasic waveforms may achieve more desirable therapeutic effects because the same charged cell membrane potential is maintained for a longer duration. However, monophasic waveforms stimulate adjacent muscle groups more than biphasic waveforms.

Fig. 21F illustrates a further example of a waveform with monophasic pulses. Here, four different types of packets are shown in a single chart for centralized illustration. The first packet 402 consists of pulses of equal voltage and pulse width, with no switching time or phase-to-phase delay (because the pulses are monophasic) and a period delay equal to the active time. In some cases, the cycle delay duration of a given pulse may be greater than or equal to the active time. Thus, the first packet 402 consists of three monophasic pulses 430, each pulse including a positive peak. In case the dead time is equal to the active time, the waveform may be considered unbalanced, where the fundamental frequency represents 2 times the period of the active time and no dead time. The second packet 404 consists of monophasic pulses 430 (as in the first packet 402) of equal voltage and pulse width, with a larger period delay. The third packet 405 consists of monophasic pulses 430 (as in the first packet 402) of equal voltage and pulse width, with even greater cycle delay. The fourth packet 407 is composed of monophasic pulses 430 (as in the first packet 402) of equal voltage and pulse width, with the period delay still greater.

In some embodiments, the unbalanced waveform is achieved by delivering multiple pulses in one polarity before an unequal number of pulses that are inverted into the opposite polarity. Fig. 21G illustrates a further example of a waveform having such a phase imbalance. Here, four different types of packets are shown in a single chart for centralized illustration. The first packet 402 consists of four cycles with equal voltage and pulse width, however, opposite polarity pulses are mixed with monophasic pulses. Thus, the first period includes a positive peak 408 and a negative peak 410. The second period is monophasic, comprising a single positive pulse, without a subsequent negative pulse 430. And then repeated. The second packet 404 consists of a mixture of biphasic and monophasic periods (as in the first packet 402), however the pulses have unequal voltages. The third packet 405 consists of mixed biphasic and monophasic periods (as in the first packet 402), however the pulses have unequal pulse widths. The fourth packet 407 is composed of mixed biphasic and monophasic pulses (as in the first packet 402), however the pulses have unequal voltages and unequal pulse widths. Thus, various combinations and permutations are possible. Fig. 21H illustrates an example of a waveform having an imbalance in both the positive voltage and the negative voltage. Here the packet is shown as having a first positive pulse peak 408 and a first negative pulse peak 410, the first positive pulse peak 408 and the first negative pulse peak 410 having a voltage greater than a second positive pulse peak 408 'and a second negative pulse peak 410'. These different periods repeat throughout the packet.

With respect to the utility of unequal waveforms, the unbalanced TMP operation achieved reduces the effects of biphasic cancellation. There is a correlation between the degree of imbalance, the close to complete imbalance of the unipolar waveform, and the TMP operating strength. This will result in a proportional relationship between the extent of the therapeutic effect and the extent of muscle contraction. Thus, a waveform that is close to being more unbalanced will allow the biphasic waveform to achieve a greater therapeutic effect at the same voltage and frequency (if applicable) than those produced by a purely balanced biphasic waveform. For example, the therapeutic effect caused by a sequence of pulse lengths in the packet, such as 830ns-415ns-830ns, will cause the pulses that make up the second half of the cycle to be half the duration of the original phase. This will limit the induction of TMP manipulation during the second phase of the cycle, but will also generate less reverse TMP, resulting in a stronger original polarity effect at the original length during the subsequent cycle. In another example, the "positive" part of the waveform may be 2500V and the "negative" part 1500V (2500-1250-2500-etc. V), which will induce a comparable TMP polarization effect as described for the pulse duration. In both cases, operation of opposite polarity strength will result in a stronger TMP operation accumulated over the periodic positive pulses. This will therefore reduce the effect of biphasic ablation and will produce a stronger therapeutic effect than the 830-830-830ns or 2500-2500-2500V regimen, despite less total energy deposition delivered to the tissue. In this way, when TMP manipulation is essential to the therapeutic mechanism of action, less total energy can be delivered to the tissue, but the desired therapeutic effect is elicited.

Further expanding, a fully unbalanced waveform will not include any components of opposite polarity, but will still likely include only a brief portion of the pulse delivered in the positive phase. For example, an example of this is a packet containing a positive polarity of 830ns, a pause of 830ns with no energy delivery, then another positive polarity of 830ns, and so on. The same approach is true whether pulse length imbalance or voltage imbalance is considered, since the absence of a negative pulse is equivalent to setting any of these parameters to zero for the "negative" portion.

However, proper therapy delivery takes into account the advantages provided by the biphasic waveform, i.e., the reduction in muscle contraction caused by biphasic elimination will also be reduced. Thus, the appropriate degree of therapeutic effect is balanced with the acceptable degree of muscle contraction. For example, the ideal voltage imbalance may be 2500-1000-2500-. V, or 2500-2000-2500-. V; or 830-100-830-. Ns, or 830-500-830-. Ns.

It will be appreciated that in some embodiments the shape of the pulses is sinusoidal rather than square. One benefit of the sinusoidal shape is that it is balanced or symmetrical, so the shape of each phase is equal. Balancing may help reduce undesirable muscle irritation. It will be appreciated that in other embodiments, the pulses have a decaying shape waveform.

Alternative delivery methods

As mentioned previously, in most embodiments, access is minimally invasive and relies on an endoluminal approach. However, it will be appreciated that other methods may be used in some circumstances, such as percutaneous, laparoscopic or open surgical methods.

In some embodiments, when accessed percutaneously, the shaft 106 of the device 102 passes through a delivery device that penetrates the skin layer into the underlying tissue. In some embodiments, the delivery device includes a needle that is inserted through the skin and directed toward the target tissue. The shaft 106 is then advanced through the needle. In some embodiments, the shape of probe tip 502 facilitates penetration of tissue, such as a pointed shape. Thus, shaft 106 may be advanced through tissue to a desired location therein. Once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue. It will be appreciated that the probe tip 502 can also be advanced from the shaft 106 into tissue and/or the conductive element 560 can be advanced into tissue, with energy delivered from the conductive distal member 560.

In other embodiments, when accessed percutaneously, the shaft 106 of the device 102 is rigid so as to be able to penetrate the skin layer without the use of a delivery device. In such embodiments, probe tip 502 is generally shaped to facilitate penetration of tissue, such as a pointed shape. Thus, the shaft 106 is itself advanced into the tissue to a desired location therein. Once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue. It will be appreciated that the probe tip 502 can also be advanced from the shaft 106 into tissue and/or the conductive element 560 can be advanced into tissue, with energy delivered from the conductive element 560.

In the laparoscopic approach, the shaft 106 of the device 102 is passed through a laparoscope that has been inserted through a small incision. These small incisions can reduce pain, reduce bleeding, and shorten recovery time compared to open surgery. In some embodiments, the shape of probe tip 502 facilitates penetration of tissue, such as a pointed shape. Thus, shaft 106 may be advanced through tissue to a desired location therein. Once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue.

In open surgical methods, the shaft 106 of the device 102 may also pass through the delivery device, or the device 102 may penetrate tissue directly. In either case, once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue.

Heart synchronization

In some embodiments, the energy signal is synchronized with the cardiac cycle of the patient to prevent arrhythmia induction. Therefore, the cardiac cycle of a patient is typically monitored using an Electrocardiogram (ECG). Referring to fig. 22, a typical ECG trace 600 includes a repeating cycle of a P-wave 602 representing atrial depolarization, a QRS complex 604 representing ventricular depolarization and atrial repolarization, and a T-wave 606 representing ventricular repolarization. To safely deliver energy within the airway near the heart, synchronization between energy delivery and the patient's cardiac cycle is employed to reduce the risk of arrhythmia. High voltage energy can trigger premature action potentials within the myocardium as the delivered energy increases permeability of the myocardial cell membrane, allowing ion transport, which can lead to arrhythmias, particularly ventricular fibrillation. To avoid arrhythmias, electrical energy is delivered to the airway in a manner that exceeds the "vulnerable period" of the heart muscle. The vulnerable period of the ventricular muscle is represented on the electrocardiogram by the entire T-wave 606 during one cardiac cycle (heartbeat). Typically, for ventricular myocardium, the vulnerable period coincides with the middle and end stages of the T-wave 606. However, when high energy pulses are delivered close to the ventricles, the vulnerable period may occur a few milliseconds before the heartbeat. Thus, the entire T-wave can be considered to be in the vulnerable phase of the ventricles.

The remainder of the cardiac cycle is the P-wave 602 and QRS complex 604, which both include periods when the atrial or ventricular muscles are not sensitive to stimulation by high voltage energy. If a high voltage energy pulse is delivered during the refractory period of the muscle, the proarrhythmic potential can be minimized. The ST segment 608 (interval between ventricular depolarization and repolarization) and TQ interval 610 (interval including the end of the first cardiac cycle and the midpoint of the second cardiac cycle) of the first cardiac cycle are periods during which high voltage energy can be delivered without inducing arrhythmia due to the myocardial depolarization state (refractory period). Fig. 22 includes a shaded box indicating an example portion of the cardiac cycle in which energy may be safely applied.

It is understood that in some embodiments, the assembly 170 for obtaining an electrocardiogram is integrally formed as part of the generator 104. If the heart monitor is limited to acquiring up to 5 lead ECGs, it may be beneficial to incorporate additional leads into the system. This would further eliminate the need to use the communication port 167 to receive cardiac synchronization pulses. Instead, the processor 154 may be configured to directly detect the R-wave and evaluate the integrity of the entire QRS complex.

As used herein, the terms "about" and/or "approximately" when used in connection with a number and/or a range generally refers to those numbers and/or ranges that are close to the recited number and/or range. In some instances, the terms "about" and "approximately" can mean within ± 10% of the exemplified value. For example, in some cases, "about 100[ units ]" can mean within ± 10% of 100 (e.g., from 90 to 110). The terms "about" and "approximately" may be used interchangeably.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (65)

1. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy provides therapy to the tissue, wherein the pulsed electric field energy is generated from a waveform comprising one or more pulse packets for providing the therapy and comprising one or more delay periods to operate or reduce or avoid one or more secondary effects.

2. The system of claim 1, wherein the one or more secondary effects comprise bubble formation.

3. The system of any of the above claims, wherein each of the pulses in the one or more pulse packets has a conduction time in the range of 0.5 to 20 microseconds.

4. The system of any of claims 1-3, wherein each of the pulses in the one or more pulse packets has a continuous on-time of up to 5 microseconds.

5. The system of any of the above claims, wherein a duty cycle of each of the pulses is less than or equal to 2.5%.

6. The system of any of the above claims, wherein the delay period is greater than or equal to 1 microsecond.

7. The system of claim 6, wherein the delay period is in the range of 1 to 250 microseconds.

8. The system of claim 6, wherein the delay period is in the range of 10-100 microseconds.

9. The system of claim 6, wherein the delay period is greater than or equal to 100 microseconds.

10. The system of claim 6, wherein the delay period is greater than or equal to 250 microseconds.

11. The system of claim 6, wherein the delay period is greater than or equal to 1000 microseconds.

12. The system of claim 1, wherein the one or more secondary effects comprise a discharge event.

13. The system of claim 12, wherein the discharge event comprises an arc from at least one of the at least one electrode.

14. The system of any of claims 12-13, wherein each of the pulses in the one or more pulse packets has a conduction time in a range of 1 to 50 microseconds.

15. The system of any of claims 12-13, wherein each of the pulses in the one or more pulse packets has a continuous on-time in a range of up to 20 microseconds.

16. The system of any of claims 12-15, wherein a duty cycle of each of the at least one pulse packet is less than or equal to 20%.

17. The system of claim 12, wherein the electrical discharge event comprises generation of a pressure wave against the tissue.

18. The system of claim 17, wherein the pressure waves are sufficient to generate a cavity within the tissue.

19. The system of claim 18, wherein a duty cycle of each of the at least one pulse packet is less than or equal to 50%.

20. The system of any of claims 18-19, wherein each of the pulses in the one or more pulse packets has a conduction time in a range of 10 to 100 microseconds.

21. The system of any of claims 18-19, wherein each of the pulses in the one or more pulse packets has a continuous on-time of up to 50 microseconds.

22. The system of any of claims 12-21, wherein the delay period is greater than or equal to 1 microsecond.

23. The system of claim 22, wherein the delay period is in the range of 1 to 500 microseconds.

24. The system of claim 22, wherein the delay period is in the range of 10-250 microseconds.

25. The system of claim 1, wherein the one or more secondary effects comprise contraction of a muscle.

26. The system of claim 25, wherein the at least one electrode is configured to create a lesion having a width, and wherein reducing or avoiding contraction of the muscle causes the at least one electrode to maintain a position in which it moves no more than 25% of the width.

27. The system of any of claims 25-26, wherein the delay period is greater than or equal to 5 milliseconds.

28. The system of claim 27, wherein the delay period is greater than or equal to 10 milliseconds.

29. The system of claim 27, wherein the delay period is in a range of 5 milliseconds to 1 second.

30. The system of claim 27, wherein the delay period is in the range of 5 to 10 milliseconds.

31. The system of any of claims 25-30, wherein the one or more pulse packets comprise at least two packets separated by a packet delay period of at least 30 milliseconds.

32. The system of claim 31, wherein each of the packets is separated by a packet delay period of at least 30 milliseconds.

33. The system of any of the above claims, wherein the pulse comprises a biphasic pulse and the delay period comprises an interphase delay between positive and negative phases of the biphasic pulse.

34. The system of any of the above claims, wherein the delay period comprises an inter-packet delay.

35. The system of claim 34, wherein the inter-packet delay is in the range of 30-5000 milliseconds.

36. The system of claim 35, wherein the inter-packet delay is 30-40 milliseconds.

37. The system of claim 35, wherein the inter-packet delay is 3000-5000 milliseconds.

38. The system of any of the above claims, wherein the delay period comprises an inter-pulse delay.

39. The system of any of the above claims, wherein the waveform comprises one or more beams, wherein each beam comprises two or more packets.

40. The system of claim 39, wherein each bundle comprises three packets, and wherein each bundle is spaced to facilitate delivery within the ST interval of the patient's heart rhythm.

41. The system of claim 39, wherein the delay period comprises an inter-beam delay.

42. The system of any of the above claims, wherein the waveform has a voltage amplitude of 500 to 4,000 volts.

43. The system of any of the above claims, wherein the waveform has a frequency of 300-800 kHz.

44. The system of any of the above claims, wherein each of the one or more packets has 10-200 biphasic pulses.

45. The system of any of the above claims, wherein each of the one or more packets has 20-50 biphasic pulses.

46. The system of any of the above claims, wherein the treatment comprises 5 to 100 packets.

47. The system of any of the above claims, wherein the treatment comprises 10 to 60 packets.

48. The system of any of the above claims, further comprising a remotely located dispersive electrode positionable so as to deliver the energy in a monopolar fashion.

49. A system for treating a tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy provides therapy to the tissue, wherein the pulsed electric field energy is generated from a waveform that includes one or more pulse packets for providing the therapy and includes one or more delay periods that avoid a peak temperature in the tissue that would be reached by delivery of the energy without the one or more delay periods.

50. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy provides therapy to the tissue, wherein the pulsed electric field energy is generated by a waveform comprising one or more packets of pulses for providing the therapy, wherein each pulse has a pulse length and at least one of the at least one packet comprises a delay having a delay period that is at least twice the pulse length.

51. The system of claim 50, wherein the delay period is at least ten times the pulse length.

52. The system of any of claims 50-51, wherein the at least one packet has a packet length that is at least 50 times the delay period.

53. The system of claim 52, wherein the at least one packet has a packet length that is at least 100 times the delay period.

54. The system of any one of claims 50-53, wherein the delay comprises an inter-pulse delay.

55. The system of claim 54, wherein the pulse is a biphasic pulse and the inter-pulse delay is an inter-period delay.

56. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy provides therapy to the tissue, wherein the pulsed electric field energy is generated from a waveform comprising at least one biphasic pulse packet for providing the therapy, wherein each biphasic pulse comprises an inter-phase delay in the range of 250 to 1000 microseconds.

57. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy provides therapy to the tissue, wherein the pulsed electric field energy is generated from a waveform comprising 2-60 pulse packets for providing the therapy, wherein each pulse packet comprises at least one delay period in a range of 250 to 1000 microseconds.

58. A system for treating a tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy provides therapy to the tissue, wherein the pulsed electric field energy is generated from a waveform comprising at least one pulse packet having a delay period, wherein the at least one packet has a packet length that is at least 50 times the delay period.

59. A system for treating tissue of a patient, comprising:

at least one electrode positionable adjacent the tissue; and

a generator in electrical communication with the at least one electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy provides therapy to the tissue, wherein the pulsed electric field energy is generated by a waveform comprising at least one packet of pulses with a duty cycle of each pulse less than or equal to 50% in order to reduce or avoid one or more secondary effects.

60. The system of claim 59, wherein the one or more secondary effects comprise cavity formation in the tissue.

61. The system of claim 59, wherein the duty cycle of each pulse is less than or equal to 20%.

62. The system of claim 61, wherein the one or more secondary effects comprise a discharge event.

63. The system of claim 59, wherein the duty cycle of each pulse is less than or equal to 2.5%.

64. The system of claim 63, wherein the one or more secondary effects comprise bubble formation.

65. A system for treating tissue, comprising:

an electrode positionable adjacent the tissue; and

a generator in electrical communication with the electrode, wherein the generator comprises at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the pulsed electric field energy treats the tissue, wherein the pulsed electric field energy is generated from a waveform having a particular delay period between selected pulses, the particular delay period selected to affect gas formation, external discharge, muscle contraction, cavity formation, and/or temperature rise.