Treatment of an internal space using a plasma generator

Abstract

The plasma delivery tip of a medical-grade plasma generator is configured to exclude potential contaminants while operating within a body cavity. In some embodiments, the delivery tip is provided with an antechamber that is optionally filled with ionized gas pressure to prevent contamination. Some embodiments include one or more internal and / or external valves configured to prevent proximal ingress of contaminants to the longitudinal position of the discharge electrode or into the gas delivery lumen. In some embodiments, the expandable distal portion of the plasma delivery tip acts as a valve that seals when closed and expands when open to create an expanded antechamber through which the plasma is delivered.

Description

Technical Field

[0001] [Related Applications] This application claims the benefit of priority under 35 USC 119(e) to U.S. Provisional Patent Application No. 62 / 991,649, filed on March 19, 2020, the content of which is hereby incorporated by reference in its entirety.

[0002] This application is one of four co-pending applications, including the PCT applications having Attorney Docket Nos. 85937, 85988, and 85987, the content of each of which is hereby incorporated by reference in its entirety.

Background Art

[0003] In some embodiments, the present invention relates to the field of low-temperature atmospheric plasma generation, and more particularly, to the delivery of low-temperature plasma into body lumens.

[0004] Plasma is generally a general term encompassing a composition of ionized gas that includes free electrons and ions, as well as neutral atoms and molecules, and often free radicals. Plasma is generated by passing a gas through a discharge, by which gas atoms or molecules can be excited and ionized. Over the past decade, there has been a growing interest in plasma applications. Some applications are based on dielectric barrier discharge (DBD) for the generation of low-temperature non-thermal plasma, i.e., so-called "cold" plasma. Such low-temperature plasma is a low-ionization non-thermal plasma generated under atmospheric pressure conditions. Low-temperature plasma has been found to be useful for various applications in medicine and industry.

Summary of the Invention

Means for Solving the Problems

[0005] According to one aspect of some embodiments of the present disclosure, a plasma delivery tip of a medical grade plasma generating device is provided. The plasma delivery tip is defined within a peripheral wall, has a proximal-distal axis, and along which a flow of ionized gas flows into a distal opening of a gas delivery lumen, a discharge electrode that transmits a high voltage to the flow of ionized gas when attached to a high voltage source, and a valve positioned to prevent proximal entry of contamination into the longitudinal position of the discharge electrode along the proximal-distal axis.

[0006] According to some embodiments of the present disclosure, the valve is arranged to prevent entry of liquid material through the opening when closed.

[0007] According to some embodiments of the present disclosure, the valve is disposed within the gas delivery lumen between the opening and the discharge electrode.

[0008] According to some embodiments of the present disclosure, the valve includes a one-way valve that opens under pressure from the flow of ionized gas.

[0009] According to some embodiments of the present disclosure, the valve includes an actuated valve that is actuated separately from the pressure from the flow of ionized gas.

[0010] According to some embodiments of the present disclosure, the opening of the gas delivery lumen is inclined obliquely with respect to the proximal-distal axis.

[0011] According to some embodiments of the present disclosure, the valve includes a leaf valve, a slit valve, or a flap valve.

[0012] According to some embodiments of the present disclosure, the valve is configured to deflect a plasma plume generated within the flow of ionized gas by a high voltage pulse to an angle that varies according to the opening degree of the valve.

[0013] According to some embodiments of the present disclosure, the plasma delivery tip includes an outer wall that surrounds the peripheral wall of the gas delivery lumen and is radially spaced from the peripheral wall of the gas delivery lumen to define a gap through which the ionized gas is scavenged after delivery to the discharge electrode.

[0014] According to some embodiments of the present disclosure, the peripheral wall of the gas delivery lumen also defines a conduit through which the ionized gas is scavenged after delivery to the discharge electrode.

[0015] According to some embodiments of the present disclosure, the valve includes a folded ante-chamber of the gas delivery lumen disposed along a proximal-distal axis between the discharge electrode and the opening when closed.

[0016] According to some embodiments of the present disclosure, the ante-chamber expands to have an inner diameter that is at least 1.5 times greater than the inner diameter of the ante-chamber in the folded configuration.

[0017] According to some embodiments of the present disclosure, the valve includes a calyx having one or more leaves attached externally to the plasma delivery tip on its proximal side.

[0018] According to some embodiments of the present disclosure, the leaves are split from each other when expanded to expose the opening of the gas delivery lumen.

[0019] According to some embodiments of the present disclosure, the expanded ante-chamber defines an opening of the gas delivery lumen on the distal side of the ante-chamber.

[0020] According to some embodiments of the present disclosure, the folded ante-chamber includes a rigid and sharp tip configured to penetrate tissue.

[0021] According to some embodiments of the present disclosure, the discharge electrode extends around at least a portion of the periphery of the gas delivery lumen.

[0022] According to some embodiments of the present disclosure, the discharge electrode is arranged together with the gas delivery lumen and surrounded by the flow of the ionized gas.

[0023] According to some embodiments of the present disclosure, the outer diameter of the plasma delivery tip is less than 5 mm.

[0024] According to one aspect of some embodiments of the present disclosure, a method of operating a plasma delivery tip is provided, which includes contaminating the interior of the gas delivery lumen of the plasma delivery tip with a liquid and operating the plasma delivery tip to generate plasma.

[0025] According to some embodiments of the present disclosure, the lumen has a diameter of less than 5 mm.

[0026] According to one aspect of some embodiments of the present disclosure, a method of operating a plasma delivery tip is provided, the method including guiding the plasma delivery tip into an aqueous fluid in contact with a target surface, directing plasma from the plasma delivery tip into the fluid, and redistributing reactive species induced in the fluid by the plasma to the target surface.

[0027] According to some embodiments of the present disclosure, the target surface is inaccessible to the plasma directed from the plasma delivery tip.

[0028] According to some embodiments of the present disclosure, redistributing includes supplying a fluid that replaces the aqueous fluid.

[0029] According to some embodiments of the present disclosure, redistributing includes agitating the aqueous fluid.

[0030] According to some embodiments of the present disclosure, redistributing includes enabling the aqueous fluid to be redistributed to at least a partially dried area of the target surface.

[0031] According to some embodiments of the present disclosure, the method includes drying at least a partially dried region of a target surface.

[0032] According to one aspect of some embodiments of the present disclosure, a plasma delivery tip of a medical grade plasma generating device is provided, the plasma delivery tip having a proximal-distal axis and a gas delivery lumen defined within a peripheral wall that acts as a conduit for a flow of ionizable gas exiting an opening of the gas delivery lumen, and receiving a high voltage pulse from an electrical connection to a power source of the plasma generating device and configured to transmit the pulse to the flow of ionizable gas through a plasma generation region of the gas delivery lumen having a first inner diameter, wherein the inner diameter of the opening is larger than the first inner diameter.

[0033] According to some embodiments of the present disclosure, a distal portion of the distal peripheral wall of the discharge electrode is foldable.

[0034] According to some embodiments of the present disclosure, the peripheral wall includes a thinner wall portion distal to the discharge electrode and a thicker wall portion within the plasma generation region.

[0035] According to some embodiments of the present disclosure, the thinner wall portion and the thicker wall portion are fixed relative to each other along the proximal-distal axis.

[0036] According to some embodiments of the present disclosure, the thinner wall portion and the thicker wall portion are movable relative to each other along the proximal-distal axis via a maximum relative displacement of 50 mm or less.

[0037] According to one aspect of some embodiments of the present disclosure, a method of operating a plasma delivery tip is provided, the method including guiding the plasma delivery tip to a target while a closure disposed to prevent contamination of an internal region of the delivery tip extending along the discharge electrode remains closed, opening the closure, and operating the discharge electrode to generate a cold plasma.

[0038] According to some embodiments of the present disclosure, the closure includes a valve, and opening the valve includes delivering a flow of ionized gas through the plasma delivery tip to press against the valve.

[0039] According to some embodiments of the present disclosure, the method includes pressing the distal side of the plasma delivery tip against the target before opening the closure.

[0040] According to some embodiments of the present disclosure, the closure is performed before delivery.

[0041] According to one aspect of some embodiments of the present disclosure, a method of operating a plasma delivery tip is provided, the method including guiding the plasma delivery tip to the target, pressing the distal side of the plasma delivery tip against the target, expanding the distal portion of the plasma delivery tip, and operating the plasma delivery tip to generate a low-temperature plasma.

[0042] According to some embodiments of the present disclosure, expanding includes increasing the pressure within the distal portion while the distal portion seals against the target.

[0043] According to one aspect of some embodiments of the present disclosure, a method of operating a plasma delivery tip in vivo is provided, the method including guiding the plasma delivery tip to a position within a body lumen, during the guidance of the plasma delivery tip in vivo, blowing ionized gas from the distal opening of the gas delivery lumen of the plasma delivery tip using a liquid, and starting the ionization of the ionized gas within the body lumen while continuing the blowing.

[0044] According to aspects of some embodiments of the present disclosure, there is provided a medical-grade plasma generating device including a probe sized for insertion into a selected portion of a body lumen and having a discharge electrode and a plasma generating distal tip including an opening through which an ionized gas flows, and a plurality of balloons passing through at least one through which the probe extends, the plurality of balloons being sized and arranged to expand within a selected portion of the body lumen and seal the opening therebetween.

[0045] According to some embodiments of the present disclosure, the balloon is sized to seal a portion of a blood vessel lumen.

[0046] According to some embodiments of the present disclosure, the balloon is sized to seal a portion of an intestinal lumen.

[0047] According to one aspect of some embodiments of the present disclosure, there is provided a method of delivering plasma to a selected portion of a body lumen that conveys a liquid, the method including inserting a plasma delivery opening of a plasma generating portion of a plasma delivery device to reach a selected portion of the body lumen, sealing the selected portion distal and proximal to the opening, removing liquid from the selected portion, and delivering plasma to the selected portion through the plasma delivery opening.

[0048] According to some embodiments of the present disclosure, sealing includes inflating balloons distal and proximal to the opening.

[0049] According to aspects of some embodiments of the present disclosure, there is provided a method of delivering plasma to an internal body region, the method including inserting first and second probes into the body region and using the first and second probes to deliver an ionized gas, ionize the gas to generate plasma, and scavenge the ionized gas, wherein the first probe is used to perform no more than two of a delivery gas, an ionized gas, and a scavenging gas, and the second probe performs at least one of the remaining of a delivery gas, an ionized gas, and a scavenging gas.

[0050] According to some embodiments of the present disclosure, a first probe is delivered to a body region via a flexible probe guided through a body cavity, and a second probe is delivered to the body region via a rigid probe inserted percutaneously.

[0051] According to some embodiments of the present disclosure, the method also includes delivering an auxiliary fluid to an internal body region, the auxiliary fluid including a molecular species that reacts with an ionized ionized gas.

[0052] According to some embodiments of the present disclosure, at least one of the first probe and the second probe is positioned by a robot.

[0053] According to one aspect of some embodiments of the present disclosure, there is provided a medical grade plasma generating device including a probe sized to be inserted into a selected portion of a body lumen and having a plasma generating distal tip including a discharge electrode and an opening through which an ionized gas flows, and a switching valve positioned proximal to the plasma generating distal tip and operable to switch between delivering the ionized gas into the lumen of the probe and delivering another gas into the lumen of the probe.

[0054] According to one aspect of some embodiments of the present disclosure, there is provided a method of generating plasma within a body lumen, the method including generating plasma from an ionized gas flowing through an opening of a plasma generating probe into the body lumen, stopping the flow of the ionized gas, delivering an auxiliary fluid through the opening of the plasma generating probe into the body lumen, and restarting the generation while the plasma generating probe remains within the body lumen.

[0055] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present disclosure, exemplary methods and / or materials are described below. In case of conflict, the present patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0056] As will be understood by one of ordinary skill in the art, aspects of the present disclosure can be embodied as a system, method, or computer program product. Accordingly, aspects of the present disclosure can take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, microcode, etc.), or an embodiment combining software and hardware aspects that can generally be referred to herein as a “circuit,” “module,” or “system” (e.g., a method can be implemented using a “computer circuit”). Further, some embodiments of the present disclosure can take the form of a computer program product embodied in one or more computer-readable media having computer-readable program code embodied thereon. The implementation of the methods and / or systems of some embodiments of the present disclosure can include performing and / or completing selected tasks manually, automatically, or a combination thereof. Further, according to the actual instrumentation and equipment of some embodiments of the methods and / or systems of the present disclosure, some selected tasks can be implemented by hardware, by software, by firmware, and / or a combination thereof, such as using an operating system.

[0057] For example, the hardware for performing a selected task according to some embodiments of the present disclosure may be implemented as a chip or a circuit. As software, the selected task according to some embodiments of the present disclosure may be implemented as a plurality of software instructions executed by a computer using any suitable operating system. In some embodiments of the present disclosure, one or more tasks executed by a method and / or a system relate to a data processor that operates using a group of digital bits, such as a computing platform for executing a plurality of instructions, and are executed by a data processor (also referred to herein as a "digital processor"). Optionally, the data processor includes volatile memory for storing instructions and / or data, and / or non-volatile storage devices for storing instructions and / or data, such as magnetic hard disks and / or removable media. Optionally, a network connection is also provided. A display and / or user input devices, such as a keyboard or a mouse, are also optionally provided. Any of these implementations are more generally referred to herein as instances of computer circuitry.

[0058] Any combination of one or more computer-readable media may be utilized for some embodiments of the present disclosure. The computer-readable media may be a computer-readable signal medium or a computer-readable storage medium. The computer-readable storage medium may be, for example, but is not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. More specific examples (a non-exhaustive list) of the computer-readable storage medium include the following: an electrical connection having one or more wires, a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing. In the context of this specification, a computer-readable storage medium may be any tangible medium that can contain, or store a program for use by or in connection with an instruction execution system, apparatus, or device. The computer-readable storage medium may also contain, or store information for use by such a program, for example, data structured in a manner recorded by the computer-readable storage medium, such that a computer program can access it, for example, as one or more tables, lists, arrays, data trees, and / or other data structures. In this specification, a computer-readable storage medium that records data in a searchable form as a group of digital bits is also referred to as a digital memory. It should be understood that the computer-readable storage medium may optionally also be used as a computer-writable storage medium in some embodiments where it is not essentially read-only and / or in a read-only state.

[0059] As used herein, a data processor is said to be "configured" to perform data processing operations as long as it is coupled to a computer-readable medium to receive instructions and / or data therefrom, process them, and / or store the processing results in the same or another computer-readable medium. The processing performed (optionally, on data) is specified by instructions, with the effect that the processor operates in accordance with the instructions. The operations of the processing may additionally or alternatively be referred to by one or more other terms, such as compare, estimate, determine, calculate, identify, associate, store, analyze, select, and / or transform. For example, in some embodiments, a digital processor receives instructions and data from a digital memory, processes the data in accordance with the instructions, and / or stores the processing results in the digital memory. In some embodiments, "providing" the processing results includes one or more of transmitting, storing, and / or presenting the processing results. Presenting optionally includes presenting on a display, presenting audibly, printing on a printout, or otherwise providing the results in a form accessible to human sensory capabilities.

[0060] A computer-readable signal medium may include, for example, a propagated data signal embodying computer-readable program code therein, either baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electromagnetic, optical, or any suitable combination thereof. A computer-readable signal medium may be any computer-readable medium that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

[0061] The program code embodied on a computer-readable medium and / or the data used thereby may be transmitted using any suitable medium, including but not limited to wireless, wireline, fiber optic cable, RF, etc., or any suitable combination of the foregoing.

[0062] The computer program code for performing operations for some embodiments of the present disclosure may be written in any combination of one or more programming languages, including object-oriented programming languages such as Java, Smalltalk, C++, and conventional procedural programming languages such as the "C" programming language or similar programming languages. The program code can be executed entirely on the user's computer, partially on the user's computer, as a stand-alone software package, partially on the user's computer, partially on a remote computer, or entirely on a remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer via any type of network including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (e.g., via the Internet using an Internet service provider).

[0063] Some embodiments of the present disclosure may be described below with reference to the flowchart diagrams and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the present disclosure. It will be understood that each block of the flowchart diagrams and / or block diagrams, and combinations of blocks in the flowchart diagrams and / or block diagrams, can be implemented by computer program instructions. These computer program instructions can be provided to the processor of a general purpose computer, a special purpose computer, or other programmable data processing apparatus to create a machine that implements the means for performing the functions / operations specified in the flowchart and / or block diagram block or blocks via the processor of the computer or other programmable data processing apparatus.

[0064] These computer program instructions may also be stored in a computer-readable medium that can direct a computer, other programmable data processing apparatus, or other devices to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instructions for implementing the functions / acts specified in the block or blocks of a flowchart and / or block diagram.

[0065] The computer program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus, or other devices, thereby providing a process for implementing the functions / acts specified in the blocks of a flowchart and / or block diagram by instructions executed on the computer or other programmable apparatus or devices.

Brief Description of the Drawings

[0066] Some embodiments of the present invention will be described herein by way of example only with reference to the accompanying drawings. It is emphasized that the details shown with specific reference to the drawings are for purposes of illustration only and for an exemplary discussion of embodiments of the present invention. In this regard, the description together with the drawings will make it apparent to those skilled in the art how embodiments of the present invention may be implemented.

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[0067] In some embodiments, the present invention relates to the field of cryogenic atmospheric plasma generation, and more particularly to the delivery of cryogenic plasma into body lumens.

[0068] **Overview** One aspect of some embodiments of the present disclosure relates to a cryogenic (non-thermal) plasma generation device configured to resist the entry of contaminants while being induced within a body cavity and / or while being used to deliver plasma to biological tissue within a body cavity. The plasma generation device is configured to provide cryogenic (non-thermal) plasma to biological tissue under medical-grade temperature, safety, and sterility conditions.

[0069] Potentially, cryogenic plasma has a therapeutic effect, for example, it can act to destroy and / or induce destruction of tumor cells and / or pathogens, such as viral particles, bacteria, and / or fungi.

[0070] The mechanism of the treatment action is an area of ongoing research. As mechanisms of action for this, free radicals (e.g., OH -) For example, oxidative stress induced by free radicals has been suggested. The treatment potentially utilizes the differential sensitivity to free radicals from normal tissue and targeted tumors and / or pathogens. The treatment effect potentially depends on the interaction between the target parameters (e.g., the surrounding fluid, target size, and / or target type) and the parameters of the delivered plasma (e.g., the generated ionized species, their concentration and / or ratio). Next, the parameters of the delivered plasma can be affected by the parameters of plasma generation (e.g., the composition of the ionization medium and / or electrical parameters), as well as the parameters of the plasma plume itself (e.g., geometric shape, confinement, flow, and / or quenching).

[0071] As used herein, references to "plasma" and "plasma plume" more specifically refer to cold plasma (e.g., plasma at a temperature of 50 °C or less, preferably delivered at a temperature below body temperature, e.g., in the range of about 20 °C to 30 °C). Cold plasma is generally delivered under near-atmospheric pressure conditions and is thus also referred to as "cold atmospheric plasma" or CAP.

[0072] In some embodiments, the tissue target to which the cold plasma is delivered is inside the body. Optionally, the target is outside the body and optionally the target is not part of the body. For example, the target is optionally a calibration target, e.g., a target measured to characterize which plasma is generated at different settings of a plasma delivery device, optionally including different dielectric barrier thicknesses, different gas delivery lumen diameters, and / or different discharge electrode widths. Additionally or alternatively, the target is an assay target, e.g., a target for in vitro and / or ex vivo assays of the cold plasma effect (e.g., under conditions of different parameter settings of the plasma delivery tip) on one or more types of tumor cells, pathogen cells, virus particles, healthy cells, and / or tissue samples.

[0073] Low-temperature plasma is generated in a non-equilibrium state with respect to its environment, and its ionization state rapidly decays as charged species interact with each other, with other species in the ionized gas, and / or with molecules in the environment.

[0074] In some embodiments, a plume of low-temperature plasma (e.g., having a length of about 1 to 20 mm) is generated from a high-voltage discharge electrode that operates within an ionized gas environment generated near the target. The low-temperature plasma, which is characteristic of its non-equilibrium state, is weakly ionized. Ionization is estimated to be on the order of one part per million and / or 10 11 ~10 13 electrons / cm 3 (within a range of about 10-fold). The generated plasma is carried towards the target by the flow of the ionized gas.

[0075] The array of potential problems is related to the contamination of the plasma generation and / or delivery elements of a medical-grade low-temperature plasma delivery system.

[0076] A body cavity is a moist place where fluid carries solutes (e.g., electrolytes and / or polymers) and / or suspended particles (e.g., cells and / or their fragments).

[0077] For example, OH - free radical generation by plasma can be enhanced when the target itself is moist and optionally by the intentional introduction of gaseous H2O into the ionized gas mixture itself. Plasma delivered to a fluid (e.g., an aqueous liquid) can "activate" the fluid, such that the ionic and / or molecular species of the fluid itself become more reactive. The fluid itself can then serve as a medium that enables further redistribution of these reactive species to deliver the treatment effect to the treatment target.

[0078] However, an excessive amount of moisture in the wrong location can be potentially harmful to plasma generation and / or propagation. For example, plasma electrons lose energy and do not reach the target OH -When generating radicals, it is no longer possible to treat the target itself. Moisture can interfere with the strength of the voltage field and / or block the gas delivery lumen. This can potentially result in weakened and / or unreliable plasma generation.

[0079] Moisture (water) can be in liquid or gaseous form. Of particular concern is liquid moisture within the lumen space of the plasma delivery chip. This can affect the electric field strength encountered by the ionized gas within the plasma generation region and / or, once plasma is generated, can induce quenching of the plasma. Liquids that evaporate or are otherwise expelled can potentially leave behind electrolytes and / or suspended particles as residues that can contaminate, rapidly cool, and / or otherwise affect plasma generation and / or delivery, thus causing potential problems.

[0080] Gaseous water (e.g., humidity) is easily blown away during the onset of the ionized gas flow, but gaseous water can also enter and precipitate to form droplets. For example, cold plasma generated at room temperature can cool water-saturated body temperature gas to a sufficient degree to induce condensation.

[0081] Therefore, constructing and operating a plasma delivery chip to exclude the ingress of moisture in liquid and / or gaseous form has potential advantages.

[0082] In some embodiments, the plasma generation and "antichamber" plasma delivery tip site, including a post-generation site compartment with an open distal opening, is small, having, for example, an outer diameter in a longitudinal extent (along the proximal-distal axis) between about 1 mm and 10 mm, about 15 mm or less, about 10 mm or less, about 5 mm or less, about 4 mm or less, or about 3 mm or less. The corresponding inner diameter is smaller, optionally in the range of less than 1 mm (e.g., 0.4 - 0.8 mm), or up to about 3 - 5 mm in a somewhat larger body lumen, or up to the diameter of any of the listed outer diameters, minus an overall double-wall thickness of about 0.5 - 2 mm. Thus, a fairly small amount of liquid contamination (potentially microliters of liquid, or even less) can significantly interfere with treatment effectiveness at the target site.

[0083] In some embodiments, the inner diameter of the plasma delivery tip is further expandable, for example, by a factor of 1.5x, 2x, 3x or more (e.g., compared to the folded diameter of the plasma delivery tip and, optionally, compared to the lumen diameter of the gas delivery tube at the longitudinal position of the discharge electrode). Optionally, the expandable portion of the plasma delivery tip tapers (and becomes wider at its distal end) when expanded. This potentially increases the target area that can be treated simultaneously by the plasma delivery probe. However, it includes the potential risk of increasing exposure to fluid contamination. Upon refolding, the invading fluid can be trapped and / or diffused within the plasma delivery tip.

[0084] It should also be noted that in these dimensions, wetting and surface tension phenomena are potentially important considerations in the management of liquid entry. For example, liquids with high surface tension (e.g., many aqueous liquids) do not necessarily easily penetrate small openings unless under a pressure difference large enough to overcome the surface tension. Conversely, wetting (e.g., involving the process of capillary action) can, if allowed, be debilitating.

[0085] In some embodiments, hydrophobic materials and / or coatings are used to construct a plasma delivery tip that potentially prevents wetting and / or capillary action and enhances the contaminant removal characteristics associated with surface tension phenomena. However, it should be noted that high electric field conditions (e.g., those used to generate plasma) have several potentialities to interfere with surface tension phenomena due to electro-wetting. The plasma itself can also induce surface deformations that affect hydrophobicity.

[0086] In some embodiments, contaminant removal includes the use of the flow of the ionized gas itself to fill, pressurize, and / or dry the space within the plasma generation probe. As long as the pressure is maintained, this potentially prevents intrusion by low-pressure fluids. In some embodiments, alternative or additional protection against the intrusion of contaminants is provided.

[0087] In some embodiments, contaminant removal includes a closure (e.g., a sealing member) that is opened reversibly or irreversibly to enable the delivery of plasma. In some embodiments, the plasma delivery tip is valved (i.e., the closure comprises a valve), and the valve is disposed between the distal opening of the plasma delivery tip and a device having a discharge electrode at the site where plasma is generated. Optionally, the valve comprises the distal opening itself. In some embodiments, a closure structure is provided that is disposed distally beyond the distal opening, for example, in the form of a "calyx" that exposes the distal opening behind and / or beneath it when open. In some embodiments, a portion of the plasma delivery tip is exchangeable between a folded configuration and an expanded configuration, and the folded configuration resists or prevents the intrusion of contaminants.

[0088] Such block structures provide potential advantages in situations such as the following. - During transient high pressures, for example, when encountering an obstacle during navigation, there is a tendency to push contaminants back towards the tip. - The risk of intrusion by solid particles, which can occur when the pressure is high, for example, even when the flow itself is low. - Tight size constraints. The possibility of expanding a small space can pose a risk of tissue damage such as tearing. The limitation of the lumen cross-section of the device that can be introduced into such a space can prevent the introduction of a gas scavenging lumen to counteract the expansion. - Even with simultaneous gas scavenging, not all in vivo lumen spaces are necessarily suitable for continuous perfusion with gas, for example, due to the risk of embolism or tissue damage.

[0089] As used herein, "scavenging" a gas means exhausting the gas through such an exhaust-only conduit after the gas has performed its initial function, for example, generating a plasma plume, opening a valve, and / or drying or wetting the lumen wall.

[0090] In some embodiments, actuation (e.g., to open a valve or expand / extend a structure) is performed using the pressure from the flow of the ionized gas itself. In some embodiments, the actuation is separately controlled using, for example, a mechanical actuator, the piezoelectric effect, or another active actuation method. Optionally, the control is performed separately but cooperatively, for example, a piezoelectrically actuated valve is opened in coordination with the delivery of the ionized gas. The adjustment can be performed in an "open loop" manner (e.g., by sending commands at coordinate times) and / or by using sensing (e.g., pressure rise and / or pressure loss).

[0091] Optionally, a structure for adjusting and / or closing the distal opening of the plasma delivery tip with a valve is provided in combination, for example, a calyx (beyond the distal opening of the gas delivery lumen) and a valve (proximal to the opening) are optionally provided together.

[0092] Optionally, the structure for adjusting and / or closing the distal opening of the plasma delivery tip has an auxiliary function. For example, the distal end of the plasma delivery tip may be soft and / or blunt so as to act as a non-invasive tip (e.g., at least partially collapse, deflect, and / or deform when sufficient pressure is applied). Alternatively, in some embodiments, the distal end of the plasma delivery tip may be made rigid and / or sharp so that it can cut and / or penetrate tissue. For example, the distal end of the plasma delivery tip is optionally angled to provide a trocar-like tip. In some embodiments, the distal end (when closed) of the plasma delivery tip is converged to a sharp point configured to penetrate tissue, such as a needle.

[0093] An additional approach for managing contaminants by exclusion is to scavenge moisture from the work area to remove and / or control the concentration of aqueous molecules. In some embodiments, the plasma delivery tip is provided with a gas scavenging lumen that is optionally operable to remove the ionized gas when delivered. Gas scavenging is performed to remove gas from an ante-chamber juxtaposed to the target surface, which potentially helps to dry and / or equilibrate the level of moisture on the target surface and / or on the surface inside the ante-chamber itself (e.g., in cooperation with aqueous species delivered within the ionized gas). This potentially aids in the redistribution of reactive species to the surface of the treatment target by the activating fluid. For example, a target surface that is overly dry or overly wet may absorb and / or generate different (e.g., less efficient) reactive species than a moderately wet target surface. Optionally, the target surface is dried from environmental liquids and then wetted by the activating fluid. Potentially, initial surface drying promotes the redistribution of the activating fluid, for example, by facilitating fluid movement due to wet surface interactions.

[0094] Optionally, contamination, moisture, and fluid purge are typically performed by reversing the direction of flow within a gas delivery lumen that operates to supply an ionized gas from a source. Optionally, the gas delivery lumen alternates between generating plasma and performing aspiration. In embodiments with a valve, the valve is optionally forced open by means other than internal pressure. To avoid aspiration of new contaminants, a supply of clean gas is optionally provided at the distal end of the plasma delivery tip (e.g., via another lumen of the plasma processing apparatus, e.g., via a scavenging lumen that is alternatively used as a discharge conduit for waste ionized gas). The supply may be in excess of the aspiration. In embodiments including a valve, the supply may be provided through an opening located proximal to the valve, such that the valve may remain closed or, if the valve is open, is opened with a pressure that resists further entry of contamination. Thus, in some embodiments, the valve is positioned at a location that protects multiple lumens from contamination when closed.

[0095] In some embodiments, the plasma delivery tip is enabled to be at least partially contaminated (e.g., by a liquid) within the interior of the plasma delivery tip and is then operated to generate plasma within a body lumen. Optionally, the contamination is purged (e.g., by a gas flow) prior to initiation of plasma generation. Optionally, the contamination is confined to an interior portion of the plasma delivery tip that is sealed from a functionally sensitive area (e.g., a plasma generation site) by a valve or other barrier. In some embodiments, the inner diameter of the plasma delivery tip is less than 5 mm, less than 3 mm, or less than 1 mm, and is thus sufficiently small that even minor contamination (e.g., liquid droplets, and optionally, liquid droplets that condense from gas within the body lumen) tends to significantly impair plasma generation.

[0096] One aspect of some embodiments of the present disclosure relates to the use of a plasma-activated fluid for dispensing reactive species within a body lumen.

[0097] In some embodiments, a plasma-activated fluid (e.g., an aqueous liquid) is used to help distribute the therapeutic effects of the plasma over a larger area than can receive direct contact from the plasma plume. This can be a potential advantage for increasing the amount of area being treated (e.g., as compared to the area directly impacted by the plasma plume) and / or for enabling reactive species to reach surfaces that would otherwise be inaccessible to direct treatment by the plasma plume.

[0098] Electrons and / or ionized species in the plasma plume can potentially enter the surrounding fluid and / or interact with species in the fluid contacted by the plasma plume to “activate” the fluid. The activated fluid then contains reactive (and potentially relatively short-lived) species that can readily modify the molecules they contact, including cellular molecules. Thus, the activated fluid can propagate the therapeutic effects induced by the plasma. Accordingly, there are potential advantages to using fluid-based redistribution of plasma effects by use of a plasma-activated fluid (gas and / or liquid).

[0099] Due to their short lifetimes, the most reactive species in the plasma-activated fluid tend to rapidly decay in concentration after their initial formation. There is a potential advantage to activating the plasma-activated fluid at the treatment site, during which the transport delay during which the potential therapeutic effect is diminished by loss of reactive species is reduced.

[0100] Furthermore, there are potential advantages to controlling the movement and / or geometric shape of the activated fluid that distributes the active species. For example, a fluid in the form of a thin liquid layer can potentially provide a shorter and / or more constrained path for reaching the target. A fluid spreading from the site of introduction (e.g., by pressure and / or surface interaction) can potentially carry the reactive species and enable them to spread faster than they would by, for example, diffusion.

[0101] As used herein, the term "activation fluid" refers to a fluid that encounters (but is not introduced into) the plasma plume away from the plasma plume formation region. These fluids can include gases and / or liquids. The fluid may optionally include gas-phase species that condense into the liquid phase and / or liquid-phase species that evaporate into the gas phase. Prior to activation, these fluids are referred to herein as "ambient" fluids. Ambient fluids can include fluids that pre-exist and / or are naturally introduced into the region near the target (e.g., body fluids, intake atmosphere gas, etc.). Additionally or alternatively, ambient fluids can include fluids that are artificially introduced near the target. Optionally, the artificial introduction is by a lumen separate from the gas delivery lumen. For example, any of the gas scavenging lumens described herein can be operated optionally or additionally as a lumen for fluid introduction. Fluids introduced by the gas delivery lumen itself are considered herein to originally be "part of the plasma plume" when plasma is generated as the plasma reaches the plasma generation site. However, the gas delivery lumen can also deliver ambient fluids. For example, during periods without plasma generation, an ionized gas (or another fluid) is optionally vented to the surrounding environment, where the ionized gas can become the medium for ambient fluids that can later be activated. "Used" or "spent" ionized gas (even if it is the originally emitted portion of the plasma plume itself) can optionally be reactivated by re-encountering the current plasma plume and thus can also function as an "ambient" fluid.

[0102] Activated gaseous fluids have the potential advantage of creating a rapid and / or broad distribution of reactive species. However, gaseous fluids also tend to be associated with a relatively high volume-to-surface area ratio (as long as this ratio is not constrained by the shape of the space bounding the gaseous fluid). Activated liquid fluids (e.g., aqueous liquids) spread over the surface as a film and have the potential advantage of reducing the volume-to-surface ratio. This potentially results in a more efficient movement of reactive species through the target surface.

[0103] Furthermore, compared to the kinetics of direct condensation from the gas phase, there may be kinetic advantages for redistributing reactive species in an aqueous fluid to a semi-aqueous target such as cell tissue. For example, the disruption and / or mixing imparted by "injecting" a gaseous plasma into a liquid potentially accelerates the kinetics of initial condensation / generation of reactive species into / within the liquid, and then the activated liquid serves as a medium for redistributing the reactive species across the surface of the target.

[0104] One aspect of some embodiments of the present disclosure relates to supplying auxiliary atomic and / or molecular species alternately with a primary ionized gas. In some embodiments, the target effect of the plasma on the treated target includes molecular species (referred to herein as auxiliary species) that are not found in the ionized gas selected to generate the plasma itself. For example, the ionized gas may comprise a composition of helium, neon, and / or argon, while the plasma-mediated effect may include ions of other molecular species generated, for example, from oxygen, nitrogen, carbon dioxide, argon, and / or water. In the case of plasma treatment applied to a surface exposed to an open atmosphere, the molecular reagents from which these ionic species are generated are generally available from atmospheric molecules. However, in a sealed space such as inside a body lumen, these reagents may not be present or may be depleted before the treatment is complete. However, supplying these reagents together with the ionized gas can have the effect of changing (raising) the breakdown threshold voltage of the gas. This potentially terminates plasma generation and / or requires raising the supplied voltage to a level that exceeds what may be optimal in view of other considerations such as the power consumption rate and / or voltage tolerance capacity of the entire device components.

[0105] In some embodiments of the present disclosure, the auxiliary species is supplied periodically and alternately with the ionized gas, for example, in a period of about 20 seconds every 1 to 5 seconds for supplying the auxiliary species. The duty cycle of the ionized gas delivery may be, for example, about 70% to 99% of the time. The remaining time of the duty cycle is used to supply the auxiliary molecular species. In some embodiments, the valve is actuated by setting the timing and duty cycle of the valve operation as well.

[0106] In some embodiments, the cycle time of the duty cycle for switching between the fluid carrying the auxiliary species and the ionized gas is reduced from a full cycle of several seconds to about 1 second, or even shorter, for example, every 500 msec, 200 msec, or 100 msec. Optionally, the duty cycle is short enough such that at least two or more boluses of at least one of the different fluid compositions are present within the lumen connecting to the plasma delivery tip simultaneously with one or more boluses of the different fluid compositions. Apart from potential mixing at their boundaries, the central regions of the different boluses remain unmixed until at least after passing through the discharge electrodes and / or after the discharge into the environment. Reducing the cycle time has the potential advantage of improving the homogenization of the ionized gas by the auxiliary species and / or shortening the interval for adjusting the fluid / gas input to the system to balance the relative amounts of the ionized gas and the auxiliary species. Optionally, the homogenization is assisted by the use of baffles.

[0107] In some embodiments, the control of the power delivery is performed to coincide with the passage of the bolus of ionized gas through the discharge electrodes and to switch off when other fluids are passing through the discharge electrodes. This can be performed, in some embodiments, by placing the control of the switching and the electrical output under the command of a single controller or by having a plurality of controllers set by a common set of operating parameters, for example, parameters stored in a computer memory and / or electrical values of controls such as variable resistors.

[0108] In some embodiments, the fluid alternation includes delivery of a liquid such as saline through an ionized gas delivery lumen. The switch back to the ionized gas optionally involves and / or is preceded by delivery of a dry gas through the gas delivery lumen to assist in purging the liquid. Injection of the liquid through the ionized gas delivery lumen can be performed as a way to clean the lumen and / or to help ensure no backflow into the lumen. The liquid fluid used to clean and / or maintain cleanliness is optionally injected at selected times (not periodically) or at any suitable periodic intervals, such as described for the general case of alternating fluid injection.

[0109] In some embodiments, the gas delivering the auxiliary species also acts to ensure that the gas exhausted from the region of plasma application itself has a breakdown threshold that is too high to be inadvertently converted to plasma. This can be important, for example, when the gas is scavenged using a probe lumen that extends parallel to a conductor used to generate plasma at the tip of the probe. In some embodiments, the auxiliary gas is often supplied in a sufficient and sufficient amount to maintain a sufficient margin of breakdown voltage higher than the voltage carried by a conductor placed near the gas exhaust conduit.

[0110] One aspect of some embodiments relates to delivery of plasma to a luminal space that is normally or potentially filled with liquid, such as a blood vessel, a gastrointestinal tract segment, or a urinary tract segment. Complete immersion in an aqueous liquid is generally incompatible with plasma generation. Thus, to deliver plasma to a region within a body lumen filled with liquid, such as a blood vessel, it is potentially advantageous to provide a system capable of establishing a volume within the body lumen isolated from fluid communication with an adjacent volume, evacuating it, performing plasma treatment, and then refilling the isolated region with liquid (removing bubbles that could cause embolism) if and when the isolated volume is released again.

[0111] In some embodiments, the plasma delivery tip is provided with a deployable structure such as a balloon, which inflates or otherwise deploys to reversibly establish a fluid seal with the body lumen to establish fluid separation and can then contract after treatment is complete.

[0112] In some embodiments, the evacuation of the isolated region for treatment is accomplished by pushing gas into the region while allowing existing fluid to be evacuated in response. Optionally, the drainage is assisted by a suction pressure. Optionally, a wash fluid is used as part of the evacuation procedure to replace a viscous fluid such as blood with a less viscous fluid such as saline, and then gas is introduced to enable plasma generation. The gas may be a dry gas, which potentially helps remove liquid from the isolated volume.

[0113] Generally, a system used to isolate a region for treatment comprises a distal sealing element and a proximal sealing element, and there is an opening between the proximal sealing elements into which plasma and / or an ionized gas is introduced. Both of the two sealing elements may be an integral part of the plasma delivery tip itself, or one or both of them may be introduced and positioned separately.

[0114] Before explaining in detail at least one embodiment of the present disclosure, it is to be understood that the present disclosure is not necessarily limited to the details of the construction and arrangement of components and / or methods described in the following description and / or shown in the drawings in its application. Features described in the present disclosure, including features of the invention, may have other embodiments or may be practiced or carried out in various ways.

[0115] Plasma Processing Apparatus Now, refer to FIGS. 1A - 1B, which schematically illustrate the configuration of a plasma processing apparatus 55 according to some embodiments of the present disclosure.

[0116] In some embodiments, the plasma processing apparatus 55 includes a high-voltage power controller 60 and an ionizable gas supply source 61 interconnected to a plasma probe assembly 62. The high-voltage power controller 60 supplies an ionization voltage to the plasma probe assembly 62 via a cable 71 (e.g., a coaxial cable or another electrical conduit having a controlled impedance and shield along its length). The ionizable gas supply source 61 supplies an ionizable gas to the plasma probe assembly 62 via a tube 72. The gas supplied can include, for example, one or more noble gases such as neon, argon, or helium, and / or other gases suitable for ionization into the plasma plume. Optionally, the cable 71 and the tube 72 are integrated into a single cable unit that connects to the plasma probe assembly 62. Optionally, the high-voltage power controller 60 and the ionizable gas supply source 61 are integrally housed.

[0117] The plasma probe assembly 62 optionally includes a handle 80. The handle 80 is optionally provided with control devices 81, 82 for controlling the operation of the probe conduit 73 and / or the plasma delivery tip 66, for controlling the functions of the power controller 60, and / or for controlling the delivery of ionizable gas from the gas supply source 61. Optionally, the plasma probe assembly 62 physically integrates the power and gas delivery functions into the probe conduit without using a dedicated handle. In some embodiments, the probe conduit 73 includes both lumens (e.g., continuations of the cable 71 and the tube 72) for delivering both ionizable gas and high voltage.

[0118] In some embodiments of the present invention, the probe conduit 73 and the plasma delivery tip 66 are sized, and otherwise configured (e.g., safety configured), for delivery of cold plasma to an in vivo location. In some embodiments of the present disclosure, the plasma delivery tip is configured to be insertable into the in vivo target region through a lumen and / or opening, for example, of about 15 mm or less, about 10 mm or less, about 5 mm or less, about 4 mm or less, or about 3 mm or less. The diameter of the gas delivery lumen that delivers the ionized gas to be ionized into plasma in the plasma delivery tip and / or delivers the ionized gas itself as a plasma plume away from the plasma delivery tip is optionally in the range of about 0.4 mm to 8 mm. The portion of the plasma delivery tip that generates and shapes the plasma plume is optionally about 4 mm to 30 mm in length. A longer length is optionally used with a correspondingly higher discharge voltage to prevent dielectric breakdown.

[0119] FIG. 1A illustrates a plasma probe assembly 62 in a “stand-alone” configuration, e.g., a configuration that can be used as a catheter that can be guided by itself to reach an in vivo target. However, it should be understood that in some embodiments, the plasma probe assembly 62 is optionally used together with another device, e.g., by passing through the working channel of an endoscope or by inserting through the lumen of another catheter. The plasma probe assembly 62 is illustrated as comprising a flexible probe conduit 73, but it should be understood that the probe conduit 73 is optionally rigid and optionally straight or curved. The probe conduit 73 is optionally of any length suitable for reaching its target.

[0120] Some embodiments of the present disclosure are described as comprising a sheath or overtube having a lumen, within which an element of a plasma delivery tip advances. Optionally, the sheath is part of a probe conduit 73. Optionally, the sheath is provided as the lumen of a device into which a plasma probe assembly is inserted, such as the working channel of an endoscope or as a separately provided catheter. Embodiments illustrated and / or described without a sheath are optionally provided and / or operated using a sheath. Conversely, embodiments described using a sheath are provided and / or operated as needed, and / or are "sheathless" even though features that specifically rely on the sheath (e.g., using a portion of its lumen space as a gas and / or plasma return path) may not be available.

[0121] Power delivery to the plasma plume through the plasma delivery tip 66 is optionally in the range of about 0.1 - 10 W, 0.1 - 5 W, or 1 - 2 W (e.g., about 1.5 W). Current delivery through the plasma delivery tip is optionally in the range of about 5 - 20 mA (e.g., about 8 mA). The voltage supplied to generate the plasma is optionally in the range of about 750 - 850 V (at radio frequency). Optionally, the voltage is higher, e.g., up to about 1000 V or 1600 V. The ionization flow rate (at approximately atmospheric pressure) through the plasma delivery tip 66 is optionally in the range of about 0.1 L / min to about 9 L / min, e.g., 0.5 L / min, 2 L / min, 3 L / min, 6 L / min, 9 L / min, or another gas flow rate. The pulse repetition rate (i.e., the pulse comprising several radio frequency voltage oscillations) is optionally selected from the range of, e.g., about 100 - 600 Hz, or about 200 - 500 Hz. The pulse is optionally in the range of about 100 μs - 1000 μs, e.g., about 400 μs, 600 μs, or another pulse length.

[0122] Optionally (FIG. 1B), the plasma processing apparatus 55 may include a secondary fluid source 63 that is a source of clean pressurized air or another gas composition, such as a non-atmospheric ratio of oxygen and nitrogen. The gas composition provided may optionally include other species such as water vapor, and optionally the fluid is in a liquid form such as saline or water.

[0123] The secondary fluid source 63 can supply a second ionized gas (e.g., the ionized mixture supplied by the ionized gas source 61), but the composition supplied by the secondary fluid source 63 is not itself an ionized gas for the plasma processing apparatus 55, i.e., it is not in an unmixed form suitable for ionization by the plasma delivery chip 66 (e.g., its ionization energy is too high), which is a particular feature of some embodiments of the present disclosure. However, this composition may contain species that partially ionize or otherwise react in the presence of the plasma. In some embodiments, species that are products of these secondary reactions potentially contribute to the processing effects resulting from the plasma exposure. Delivery of the gas from the secondary fluid source 63 may be, for example, at a flow rate in the range of about 0.1 L / min to about 10 L / min, as described for the flow of the ionized gas. The liquid may be delivered at a lower rate, e.g., 0.01 L / min to 0.1 L / min, or another liquid delivery rate. Delivery of the gas and liquid may be alternated itself. Generally, the secondary fluid source 63 may itself comprise a plurality of fluid sources that can be selectively mixed and / or alternated for delivery.

[0124] In the schematic, the secondary fluid source 63 is represented as a pump, but it may be provided from another pressurized source such as a tank. The fluid provided is optionally filtered, e.g., filtered to remove biological contaminants. The secondary fluid source 63 itself is optionally provided as part of the plasma processing apparatus 55, and optionally the plasma processing apparatus is configured to receive the secondary fluid from an external source such as a hospital building's compressed air distribution system (e.g., via a tube 75).

[0125] In some embodiments, tube 72 (FIG. 1A) is replaced by a plurality of tubes 75, 77, 79 (FIG. 1B). The switching valve 64 operates, in some embodiments, to switch the gas delivered from tube 77 (connected to the ionized gas source 61) or tube 75 (connected to the secondary gas source 63) through tube 79 to the handle 80.

[0126] A potential advantage of this arrangement is that it enables the periodic injection of molecular species, which are not necessary for (or may even interfere with) the initial generation of the plasma, but can nevertheless mediate the treatment effect. These species are referred to herein as "auxiliary species". In particular, the plasma treatment effect verified by tests conducted under open atmosphere conditions potentially changes (even for the same plasma generation parameters) when the plasma is delivered to a confined space such as a body lumen. Even if there is an original level of gas such as nitrogen or oxygen, this can be depleted as plasma generation progresses or replaced (e.g., by the ionized gas). This can be applied to environmental molecular species or the molecular species of the treatment target itself.

[0127] More specifically, alternating between the two sources has the potential advantage of introducing auxiliary species into the lumen space without the need to change the mixture of ionized gas used as the primary medium for plasma generation. For example, the ionized gas from gas source 61 may be supplied for about 20 seconds every 1 - 5 seconds of the gas from secondary gas source 63 (the duty cycle is between 20:1 and 4:1). In some embodiments, another ratio, for example, a ratio of about 5:1 to 60:1, such as 10:1, 30:1, or 60:1, is used. In some embodiments, the duty cycle is from about 7:3 (70% ionized gas delivery phase) to 99:1 (99% ionized gas delivery phase). The duty cycle is optionally set according to another unit of measurement such as volume at atmospheric pressure.

[0128] The potential advantage of using unmixed ionized gas from the ionized gas supply source 61 is that the ionization energy can be kept low. For example, the voltage can remain within 30% of the threshold voltage for reliable ionization of the unmixed ionized gas. This is a potential advantage for electrical and / or thermal safety and / or the ability to maintain a small device cross-section (e.g., less than 7 mm in diameter; the wiring and insulation width itself depends on the power and voltage requirements). When the device operates near the breakdown threshold, even a small amount of auxiliary seed gas introduced may not ionize once or may have insufficient reliability. Therefore, it is preferable to completely stop the delivery of the ionized gas to enable a higher speed of delivery of the auxiliary species and a shorter interruption in the plasma generation duration.

[0129] Furthermore, in some embodiments, the spectral characteristics of the plasma are monitored to control plasma generation and / or verify that the plasma is being delivered as planned. Mixing the ionized gas with the auxiliary species can complicate this monitoring, for example, by adding spectral lines that confuse the monitoring measurements.

[0130] Nevertheless, the switching valve 64 can be optionally controlled in some embodiments to allow for partial mixing of the gases from the two gas supply sources 61, 63 during the auxiliary species delivery phase. This can make it possible to continue under sub-optimal conditions (e.g., high operating voltage and / or uncertain operating results) without completely interrupting plasma generation. Another potential use of the partial mixing is to determine (based on what percent mixing quenches plasma generation) how much above the threshold breakdown voltage at which the device is actually operating without the need to adjust the voltage itself.

[0131] In some embodiments, the duty cycle frequency is set such that the plasma delivery phase is longer than 10 seconds, for example, 20 seconds, 30 seconds, or another time. The auxiliary species delivery phase is optionally between about 0.5 and 10 seconds. The longer uninterrupted plasma delivery phase of the duty cycle can make it easier to track where the plasma is actually delivered and / or help keep the plasma plume itself stable. However, if it is too long, the auxiliary species may be depleted. Thus, the duty cycle can be adjusted according to the estimated or observed (e.g., spectroscopically observed) depletion rate of the auxiliary species.

[0132] Referring now to FIG. 2A, which schematically depicts a plasma delivery tip 66 that includes an anti-chamber 20 providing a longitudinal separation between a plasma generation site near the discharge electrode 106 and an outer volume 11 surrounding the plasma delivery tip 66, according to some embodiments of the present disclosure.

[0133] FIG. 2A provides a general schematic of a plasma delivery tip 66 having an anti-chamber 20. A peripheral wall 101A defines the anti-chamber 20. The anti-chamber 20 opens distally to the outer volume 11 and approximates an end to the plasma generation region 12 of the plasma delivery tip 66 and includes a peripheral wall 102A and particles 106 that together define several important electrical and geometric properties that affect the generation of the plasma plume 10 therein. These properties include (1) the inner diameter of the peripheral wall 102A, (2) the breakdown voltage of the dielectric barrier separating the electrode 106 from the lumen 95 of the peripheral wall 102A, and (3) the length of the electrode 106 from proximal to distal, which affect the output voltage of the plasma. The voltage is optionally supplied to the discharge electrode 106 along an electrical conduit 105 that is a coaxial cable.

[0134] In some embodiments, the peripheral wall 101A surrounds a lumen space (antechamber 20) that is larger in diameter than the space surrounded by the peripheral wall 102A. In some embodiments, the distal opening 21 of the peripheral wall 101A is located at a fixed rectangular distance from the end of the peripheral wall 102A (as long as the peripheral wall 101A remains unfolded), or within a short range (e.g., 50 mm or less, 20 mm or less, 10 mm or less, 5 mm or less, or 1 mm or less) of an adjustable longitudinal distance. Thereby, the longitudinal length of the antechamber 20 is either fixed or adjustable within a short range. This distinguishes the peripheral wall 101A from, for example, an overtube where the plasma generation region 12 can advance or retreat at any distance. The potential advantages of the antechamber 20 with a fixed length or short-range adjustable length are to prevent the plasma generation region 12 from passing through the opening 21 (which may be directly exposed to fluid contamination), and to maintain more certainty that the plasma plume 10 is generated within its range so that it can reach the opening 21 (and the plasma treatment target is optionally placed at that position).

[0135] Also, there are potential advantages that enable selection of a larger area of treatment target for processing in the plasma plume 10. For example, when the distal opening 21 is pushed up against the treatment target, the play of the plasma plume 10 potentially expands to simultaneously encompass a larger area than is available without lumen expansion. At the same time, it is possible to partially decouple the geometric parameters that govern plasma generation (in the plasma generation region 12) from the diameter of the antechamber 20. The ratio of the thickness of the peripheral wall 101A to the peripheral wall 102A (i.e., within the plasma generation region 12) is optionally 1:2, 1:3, 1:4 or more. The ratio of the wall thicknesses is optionally reversed, for example, 2:1, 3:1, 4:1, or less, which results in a narrower outlet with a constant outer diameter and potentially increases the ejection speed of the plasma plume 10. This potentially increases the mixing of the plasma plume 10 with the surrounding environmental fluid, which is a potential advantage, for example, for increasing the efficiency of fluid activation.

[0136] The peripheral wall 101A is optionally "blunt" or "sharp" (e.g., compare the embodiments of FIGS. 2B and 2C). Optionally, the resistance to folding of the peripheral wall 1010A is selected according to the expected conditions. A more resistant peripheral wall 1010A is potentially useful, for example, as a trocar for penetrating tissue, for example, optionally, arbitrarily, constructed of (polymer-coated) metal or a rigid polymer.

[0137] A softer peripheral wall 1010A is potentially useful, for example, as a non-damaging tip for steering within the boundaries of delicate body lumens. The peripheral wall 101A is optionally configured as an elastically deformable membrane having a thickness of less than 1000 μm, for example, about 500 μm, 250 μm, about 100 μm, or other thicknesses. Optionally, the peripheral wall 101A is composed of a material that is soft and easily elastically deformable at the selected thickness, for example, collapsing under an external pressure less than about 2 bar, 1 bar, 0.5 bar, 0.25 bar, 0.1 bar, 0.05 bar, or another pressure. During plasma delivery, the internal pressure generated by the inflowing gas helps, for example, to resist the collapse of the peripheral wall 101A when pushed against a target. The thick peripheral wall 102A provides support from the approximation side.

[0138] The plasma plume 10 is also optionally affected by adjusting the orientation and symmetry of the components within the plasma generation region 12. The configuration of FIG. 2A generically represents configurations such as those of FIGS. 2B-2E, where the plasma is at least partially generated around the circumference of the lumen 95 using a flow of ionized gas 8 that flows along the lumen 95 defined by a peripheral wall (the wall and / or tube of the lumen 95) in which the circumferentially arranged discharge electrodes 106 extend. It should be understood that the pressure-maintained ante-chamber 20 is optionally provided in other configurations, for example, a configuration using a discharge electrode surrounded by a flow of ionized gas as shown in FIG. 3A (without a valve).

[0139] In some embodiments, the plasma delivery tip 66 is configured to deliver plasma to a target within an environment 11 that includes aqueous molecules, water-saturated gas, and / or free liquid and is potentially liquid-immersed. However, contamination (e.g., aqueous contamination) can very rapidly quench the plasma plume and prevent its effective delivery to the target. Even if the plasma plume is not completely quenched, the parameters of plasma generation can be unpredictably altered by contamination.

[0140] In some embodiments, contamination is prevented by maintaining a constant positive pressure of the ionized gas 8 within the inner lumen of the plasma delivery tip 66 (i.e., constantly "blowing out" the ionized gas from the distal opening at the tip) to prevent contaminants from entering the chamber 20. For plasma delivery, the distal opening 21 of the ante-chamber 20 is optionally pushed up against the target and / or inserted into a lumen space that can remove interfering contaminants, in part or in whole, by, for example, the gas pressure applied by the flow of the ionized gas 8. In the case of a small lumen device (e.g., a device having a lumen diameter of 5 mm or less), the amount of gas vented while maintaining the positive pressure is potentially low enough that the problem of expansion is negligible, or otherwise, a portion of the blown-in gas is optionally captured by a return lumen.

[0141] This method of preventing backflow of liquid into the pre-chamber 20 and / or the plasma generation region 12 has the potential drawback of creating a continuous gas flow within the body lumen in which the plasma delivery tip 66 moves, and it should be noted that this is not always acceptable. For example, gas scavenging from within the lumen of the plasma delivery tip 66 may not always be available to control pressure increases. Also, for example, when the plasma delivery tip enters a particularly confined space, if the backpressure overcomes the forward pressure of the gas, a potential risk of liquid contamination remains. Further, for example, it is a potential advantage that the ionized gas flow can be freely commanded to completely stop on command to remove disturbances caused by a continuous gas flow (e.g., bubbling) that may interfere with imaging and / or process monitoring.

[0142] Referring now to FIGS. 2B-2E, which schematically depict a valved configuration of a plasma delivery tip that generates plasma using a flow of ionized gas 8 flowing along a lumen in which a circumferentially disposed discharge electrode 106 extends, according to some embodiments of the present disclosure. FIGS. 2B-2C show both the closed (left panel) and open (right panel) configurations of the same respective embodiments.

[0143] In FIGS. 2B - 2C, the wall of the anti - chamber 20 is shown by the peripheral wall 101. In FIG. 2D, the anti - chamber 20 is defined inside the peripheral wall 101A, for example, separately from the scavenging lumen 96. In FIG. 2E, the anti - chamber 20 is defined by the peripheral wall 101 (for example, when extending beyond the peripheral wall 101B), and / or the peripheral wall 101B. Corresponding to the elements within the plasma generation region 12 of FIG. 2A, there are a wire coil, a dielectric barrier layer 103 (which determines the breakdown voltage), and another insulating layer 102 that provides mechanical support and / or electrical insulation from the external electrical conduit 105, and a cut - away view of the electrode 106 implemented as the electrode 106. Optionally, these different layers are assembled together from separate components (for example, of different materials) or are formed integrally (for example, as shown in FIG. 2A). The different layers may be fixedly attached to each other or may be movable (for example, slidable and / or rotatable in the longitudinal direction).

[0144] In FIG. 2B, a one - way (check) valve 110A is located within the anti - chamber 20. When there is no flow of the ionized gas 8 in the gas delivery lumen 95, the valve 110A remains closed. During plasma generation, the valve 110A is opened so that the plasma plume 10 can project forward.

[0145] The valve 110A is more specifically represented in the drawings by a leaf valve 110A, but it should be understood that other valve designs may be substituted for this, for example, a valve design as described herein. A common feature of many such valve designs is that they leave a clear opening sufficient for the plasma plume 10 to pass through when it is open, but the valve can also be used to restrict and / or redirect the plasma plume, for example, as described in connection with FIG. 3F. Optionally, when open, the valve 110A is positioned so as to fit entirely within the anti - chamber 20. This allows the opening 21 to be fully pushed up against the target, optionally without interference from the valve.

[0146] Valve 110A is optionally opened by the pressure of the ionized gas 8 being carried out from the proximal side of valve 110A. Since it is a one-way valve, pressure from the distal side does not open valve 110A and can act as a barrier to liquid entry. Optionally, valve 110A is actuated independently of gas pressure and is described, for example, in relation to valve 110D (Figure 3E). Optionally, side vents 113 are provided in the wall of the ante-chamber 20 to allow escape of the ionized gas even when the distal opening 21 is blocked (e.g., by being pressed against the tissue being treated). In some embodiments, this can prevent an increase in backpressure from valve 110A closing or partially closing. In addition to, or instead of, opening 113, the distal circumference of the distal opening may be configured with notches providing an escape path for the gas. This also provides a potential advantage for keeping the pressure near electrode 106 more constant, for example, avoiding cycles of pressure buildup and release as a temporary blockage occurs and is overcome.

[0147] In Figure 2C, the ante-chamber 20 is formed by a trocar tip (i.e., an inclined tip defined by the obliquely angled distal opening 104). Optionally, the inclined tip helps to penetrate obstacles, such as membranes or narrow passages. The inclined tip also potentially provides a natural vent for the ionized gas in most configurations. Potentially, it holds the gas long enough to be able to remove the plasma plume 10 until liquid reaches the tissue surface targeted for treatment (especially when embedded in soft tissue).

[0148] In some embodiments, the ionized gas can dissipate (e.g., through natural or artificial body orifices). Optionally, the ionized gas is actively trapped, for example, via a channel separate from the probe conduit 73 and / or via a channel incorporated into the probe conduit 73.

[0149] Figures 2D-2E each add gas scavenging lumens 96, 97 to the general configuration of Figure 2B, allowing for a return flow 9 of ionized gas and / or liquid. In Figure 2D, the scavenging lumen 96 is a separate lumen running alongside lumen 95. In Figure 2E, the entire device of Figure 2B partially fills the peripheral wall 101B, and gas returns along the unfilled internal volume of the peripheral wall 101B.

[0150] Note that in the illustrated configuration of the embodiment of Figure 2E, the peripheral wall 101B effectively defines the distal diameter of the ante-chamber 20, and removal of the scavenged gas can occur without the gas having to exit the ante-chamber 20. Optionally, the peripheral wall 101 extends distally from the overtube 101B, and then, as described for Figure 2B, the ante-chamber 20 is defined and the gas is scavenged after exiting the ante-chamber 20. Indeed, this provides a potential advantage for selection during targeted treatment over a wider surface area, a variable aperture ante-chamber 20, or generates a narrow selection.

[0151] In some embodiments, the peripheral wall 101B constitutes an overtube (e.g., the wall of a working channel or the wall of a catheter) along which the peripheral wall 101 is free to travel longitudinally. In some embodiments, the peripheral wall 101B is located within a longitudinal relationship with the peripheral wall 101 that is fixed or adjustably restricted (e.g., adjustable up to 5 mm or 10 mm maximum). Optionally, the peripheral wall 101 is free to move radially within the peripheral wall 101B. Optionally, the peripheral wall 101 is held in a fixed or adjustable radial position, e.g., by means of spacers.

[0152] Referring now to Figures 3A-3F, which schematically depict a valved configuration of a plasma delivery tip that generates plasma using the flow of ionized gas 8 flowing along a lumen in which a discharge electrode 306 is disposed, according to some embodiments of the present disclosure. Figures 3A-3B show both the closed (left panel) and open (right panel) configurations of the same respective embodiments.

[0153] Figures 3A to 3D generally correspond to the embodiments of FIGS. 2B to 2E, respectively, except that the plasma generation region 12 is realized by flowing the ionized gas 8 around the discharge electrode 306 disposed in the lumen 96 and insulated from the ionized gas 8 by the surrounding dielectric barrier layer 303.

[0154] FIG. 3B optionally illustrates a slit valve 110B (also unidirectional), provided in any of the embodiments, e.g., instead of the leaf valve 110A, in any of FIGS. 2A - 3D.

[0155] FIG. 3E shows a longitudinally extending valve 110D optionally implemented as a piezoelectric flapper valve. Although mainly not pressure - actuated, valve 110D is optionally opened only when the local gas pressure increases (to prevent fluid ingress). For example, valve 110D is opened under the control of a control device 55 that also controls the delivery of the ionized gas. The electrical conduit 311 supplies a voltage to a valve member comprising a piezoelectric material layer 331 and a conductor layer 330. The differential bending as a result of the applied electric field opens valve 110D (assuming the valve is normally closed; the actuation for opening and closing is separately, e.g., inversely, optionally set). Such a valve configuration is optionally used, for example, with any of the valve - equipped embodiments of FIGS. 2B - 3D.

[0156] (Similar to FIG. 3B, for example) FIG. 3F comprises a one - way flap valve 110E (or another asymmetric opening valve design). Optionally, the asymmetry of the opening of valve 110E is used to affect the directionality of the plasma plume 10. The three panels (left, center, right) of FIG. 3F show three different conditions of valve opening (closed, half - open, almost fully open). Optionally, the valve opening is controlled by the pressure of the flow of the ionized gas 8. The flap of valve 110E tends to quench the frequency of plasma reaching it. One way to mitigate this is to provide the flap of valve 110E with charges that tend to refract the plasma.

[0157] Once again, it should be understood that the valve designs described herein are examples and there are no specific limitations to particular embodiments that function with only the valve configurations shown.

[0158] Referring now to FIGS. 4A - 4C, which schematically depict distal side views of different valve designs according to some embodiments of the present disclosure. FIG. 4A corresponds to a distal side view of the flap valve 110E (i.e., the valve 110E shown from the side of FIG. 3F). FIG. 4B corresponds to a distal side view of the slit valve 110B (i.e., the valve 110B shown from the side of FIG. 3B). FIG. 4B corresponds to a distal view of the leaf valve 110A (e.g., the valve 110A shown from the side in FIG. 3A).

[0159] Referring now to FIGS. 5A - 5B, which schematically depict views of an expandable tip plasma delivery chip 501 in a folded (FIG. 5A) configuration and an expanded (FIG. 5B) configuration, respectively, according to some embodiments of the present disclosure. The left panel shows a cutaway view and the right panel shows an external view. Reference is also made to FIG. 5C, which schematically depicts a cutaway of an expandable tip plasma delivery chip 504 in folded and expanded configurations according to some embodiments of the present disclosure. The folded view is shown in the left panel and the expanded view is shown in the right panel. The plasma delivery chips 501, 504 illustrate structural variations of some features of the expandable plasma delivery chip.

[0160] In some embodiments, the plasma delivery tips 501, 504 comprise a plasma generation region 12 configured to generate plasma from a flow of ionized gas 8 flowing along a lumen in which circumferentially disposed discharge electrodes extend, as described in connection with FIGS. 2B-2E herein. The plasma generation region 12 is covered by an expandable sheath 502. When folded (FIG. 5A), the expandable sheath 502 is substantially sealed against the entry of liquid through its distal end 503. When expanded, the distal end 503 of the expandable sheath 502 expands to form an ante-chamber 20 having a distal outer diameter that is optionally 1.5 times, 2 times, or greater than the more proximal outer diameter of the expandable sheath 502. This may enable the simultaneous delivery of the plasma plume 10 to a correspondingly larger area of the target surface 30. The expandable plasma delivery tips 501, 504 also provide the potential advantage of resisting clogging (e.g., during advancement of the device) since the ante-chamber 20 remains completely closed from the external environment until the distal end 503 is expanded and / or pressure is applied from the ionized gas 8. It should be noted that the treatment area is optionally reduced by further pressing the distal tips 501, 504 distally until the ante-chamber 20 created by the distal end 503 is substantially excluded from the plasma flow (and in some cases folded or even reversed) and the plasma generation region 12 itself contacts or nearly contacts the target surface 30. This potentially provides a selectably variable treatment area capability for the plasma delivery tip.

[0161] In some embodiments, the distal end 503 is normally closed and has a tendency to fold elastically and / or magnetically, for example. In some embodiments, the distal end 503 comprises elastic (e.g., nitinol, glass fiber, or polymer) struts connected by a thin webbing, or an elastic material (e.g., rubber) that has a tendency to contract into a configuration folded by its shape. In some embodiments, the conversion from the crushed tip to the expanded tip is actuated by the pressure from the flow of the ionized gas 8. Optionally or additionally, the conversion is actuated by another method, such as piezoelectric actuation bending and / or mechanical actuation (e.g., by pulling, pushing, or rotating a control member).

[0162] In some embodiments, the flare actuation of the distal end 503 utilizes thermally actuated shape memory properties. For example, the device may be elastically arranged to close at body temperature and (preferably) elastically arranged to open at a lower or higher temperature. Optionally, the distal end 503 is constructed using a shaped material that has a tendency to elastically deform towards an opposing configuration, towards a fold, or towards an expansion. Above body temperature, the balance of forces between these two is configured to induce the fold. Nitinol shape memory alloys tend to soften (and lose elasticity) below their critical temperature. In some embodiments, at least some of the crush-arranged struts are formed from nitinol that allows this softening to occur between body temperature and the temperature of the low-temperature plasma (e.g., from about 37°C to about 25°C). When softened, the balance of forces changes, allowing the distal end 503 to expand. This is optionally implemented using struts of two different nitinol alloys (i.e., having different transition temperatures), struts of a nitinol alloy acting on a rubber polymer having a tendency to take on an expanded shape, or another structure.

[0163] The target surface 30 provides closure to the opening of the ante-chamber 20 when the distal end 503 is pressed against it, helping to maintain sufficient internal pressure for inflation. At least above this pressure, the ionized gas 8 escapes from around the distal edge of the flare distal end 503 and / or is scavenged through one or more gas scavenging lumens 596 (as shown for the plasma delivery tip 501, for example) (Figs. 5A - 5B). Potentially, actively scavenging the gas helps to maintain the consistency of the "inflated" state of the expanded distal end 503.

[0164] In some embodiments, the distal end 503 is self-expanding if it is not closed, for example, by confinement with an adhesive and / or another structure. The scavenging through the gas scavenging lumen 596 may be operated under active suction. This potentially prevents gas leakage around the distal edge of the flare distal end 503. Optionally, the suction helps to remove fluid from the volume enclosed by the flare distal end 503. In some embodiments, the removed volume is established within the surrounding liquid-filled environment (e.g., a cardiac chamber, etc.), and for example, suction onto the target surface 30 is used to create an isolated chamber from which fluid is drained by suction, enabling plasma treatment to be applied.

[0165] Briefly refer to Fig. 5D, which schematically depicts a cutaway of an expandable tip plasma delivery tip 505 in its folded and expanded configurations, according to some embodiments of the present disclosure. The plasma delivery tip 505 uses a configuration of a dielectric barrier layer 303 and a plasma discharge electrode 306 disposed within the flow of the ionized gas 8. This type of plasma generating tip device is optionally configured for use with the same features of the expandable sheath 502 and distal end 503 described in relation to Figs. 5A - 5C (or Fig. 5E).

[0166] Sealing in the closed configuration of the tip of the flare distal end 503 is optionally achieved by holding it in a sufficiently closed state (e.g., because it is elastically predisposed), and any residual small opening at its tip is resistant to wetting, for example, due to the surface tension of the liquid in which it may be immersed. The tip material is optionally normally hydrophobic or treated with a hydrophobic coating. The tip portion can be configured using a thinned and / or folded webbing material to obtain a sharper tip (e.g., as shown in FIG. 5A) or a blunter tip (FIG. 5C). Optionally, a secondary seal is provided within the flare distal end 503 as a shorting leaf that merges when the distal end 503 is folded and does not interfere when the distal end 503 expands. Optionally, a secondary seal is provided outside the flare distal end, for example, in the form of a "calyx" as described in connection with FIG. 5E.

[0167] Optionally, the distal end 503 is initially closed by a bond that breaks upon expansion (e.g., an adhesive bond and / or a thin bridge of interconnecting material). Note that reliance on a one-time closure mechanism potentially impedes redeployment after device withdrawal, but this may be acceptable in some applications (e.g., single-use, single-target applications). Optionally, the distal end 503 is configured to self-adhere (e.g., by use of an internal surface coating). After expansion, the distal end 503 can be withdrawn into the confinement lumen and reset to the folded configuration by adhering the surfaces of the distal end 503 to each other to restore the closed self-sealing configuration.

[0168] Referring to FIG. 5E, a plasma delivery tip 506 with an expandable tip in folded and expanded configurations, according to some embodiments of the present disclosure, is schematically cut away and shown with a calyx 510.

[0169] The expandable plasma delivery tip 506 is generally configured like one of the expandable plasma delivery tips of FIGS. 5A-5D, and a calyx 510 is added. The calyx 510 is optionally provided, for example, to enhance sealing and / or to provide a thinner and / or sharper point relative to the distal end 503 when in a folded configuration. Note that the more tapered configuration provides potential advantages for using the plasma delivery tip 66 when guiding through a narrow body lumen and / or when penetrating, for example, solid tissue, the body lumen wall, and / or tissue membranes. The use of a sharper angle and / or a smaller opening can also help to exclude fluid due to surface tension effects.

[0170] The calyx 510 is composed of one or more leaves 510A (or, by botanical analogy, "sepals" 510A) attached to the outer approximate side of the plasma delivery tip 506. They are shaped to close the distal end of the plasma delivery tip when folded and to be split when the distal end 503 is expanded (without being joined by a fully circumferential webbing). Optionally, the calyx 510 tapers to a thin distal tip. Optionally, the leaves 510A are configured to attach to each other (and / or both) when folded. Optionally, the leaves 510A themselves are interconnected by a membrane along at least a portion of their length, potentially enhancing the ability to provide a seal excluding contaminants.

[0171] The calyx 510 is optionally made foldable, for example, elastically and / or magnetically. Optionally, the calyx 510 is held in a closed state by an adhesive (e.g., an adhesive) and / or a sacrificial membrane that breaks when the distal end 503 is expanded. Optionally, the calyx 510 is self-adhesive, for example, to help restore the folded configuration when withdrawing the closed distal tip 503 into a lumen.

[0172] Optionally, the calyx 510 is formed primarily of a soft and flexible material, for example, to provide a non-damaging tip. In some embodiments, the calyx 510 is more spiny or needle-like and includes, for example, metal and / or rigid plastic portions (optionally sharpened). This potentially aids in tissue penetration and / or manipulation, such as penetration to reach a plasma treatment target and / or preparing the plasma treatment target (e.g., dissecting in situ and / or making more permeable).

[0173] Note that the calyx 510 can be opened, for example, by internal pressure and can be considered a kind of "external valve" that prevents the entry of contaminants (while closed). Optionally, the calyx 510 is provided to seal the distal end of the non-expansion ante-chamber 20, for example, the distal end of one of the embodiments of FIGS. 2A-3F (in the case of FIGS. 2B-3F, the internal valve is optionally retained or omitted). When closed, the calyx 510 acts to prevent the entry of contaminants, but when opened, it does not define the ante-chamber 20. Rather, it peels off to a separated section, exposing the ante-chamber 20 located below and / or proximally.

[0174] Now refer to FIG. 5F, which schematically shows the deployment of the self-expanding distal end 506 from the introducer 515 according to some embodiments of the present disclosure. The distal end 506 (used for plasma delivery, for example, as described with respect to the distal end 503) has a tendency to expand elastically but is folded and held within the lumen of the introducer 515 and closed and held by the introducer 515. Panel 521 shows the distal end 506 completely covered by the introducer 515. Panels 522, 523 show the expansion during unseating of the distal end 506, and panel 524 shows that the distal end 506 is completely unseated, in contact with the target surface 30, and has a flow of ionized gas (arrow directed away from the surface 30) escaping under pressure.

[0175] Plasma Treatment Methods and Scenarios Referring to FIGS. 6A-6C, which schematically depict access modes that enable providing plasma to a plasma treatment target 1603 disposed within a lung 20 according to some embodiments of the present disclosure. Further referring to FIG. 6D, which provides a detailed view of an example of a plasma delivery configuration corresponding to FIG. 6C according to some embodiments of the present disclosure. Also referred to is FIG. 6E, which is a schematic flowchart of a method of plasma treatment within a body lumen according to some embodiments of the present disclosure.

[0176] In FIG. 6A, a probe catheter 73 is introduced through the trachea and bronchi 24 of the lung 20 and advanced (e.g., under image guidance) until it is positioned within the target 603, after which a plasma plume 10 is generated.

[0177] In FIG. 6B, the probe catheter 73 is introduced percutaneously (across the body wall 22) through an introducer 605 to a position within the target 603, where a plasma plume 10 is generated.

[0178] In FIG. 6C, the first probe 73A is introduced through the trachea and bronchi 24 of the lung 20 and advanced (e.g., under image guidance) until positioned within the target 603. The second probe 73B is introduced percutaneously (across the body wall 22) via the introducer 605 to a position within the target 603. When operated together, the probes 73A, 73B generate the plasma plume 10. Either of the probes 73A, 73B may be a voltage source, a source of fluid containing ionized gas and / or auxiliary species, and optionally may provide an exhaust lumen used to exhaust the provided fluid. The probes 73F, 73G show an alternative probe arrangement, where the probe 73G comprises a trocar and the probe 73F has a sharp tip that is steered from the tracheal / bronchial path to penetrate the lung parenchyma. Optionally, a blood vessel (especially a vein) is used for such a hybrid path and the probe is brought to the general vicinity of the target tissue via a blood vessel of sufficient diameter and then deviates through the vessel wall to reach the target itself. The positioning of any one or more of the probes can be achieved under manual control and / or by use of a robotic positioning system.

[0179] Figure 6D shows in more detail an example of how the scenario of Figure 6C can be configured. In the illustrated example, probe 73A is a hooded plasma delivery tip (optionally, such as those described in connection with Figure 5D) that is introduced through the trachea and bronchi and juxtaposed with the target surface 30 to be treated by exposure to plasma. In this example, probe 73A is supplied with voltage via discharge electrode assembly 306. Alternatively, a luminal circumferential electrode is provided as the discharge electrode. Trocar 73B is introduced percutaneously into the hood of probe 73A through surface 30, where it can perform either or both of the functions of delivering a fluid (e.g., an ionized gas) and discharging it. Plasma 10 is generated where the ionized gas flows over discharge electrode assembly 306 and is redistributed according to the gas flow, which will fill the entire hood area. The lumen of probe 73A may be used to discharge the gas supplied by probe 73B or to supply the gas discharged by probe 73B. Suction can be used to create a slight negative pressure, with the potential advantage of preventing gas leakage into the environment surrounding probes 73A and 73B and, optionally, the potential advantage of removing potential contaminants from the plasma working volume.

[0180] Alternatively, the gas may be vented around the edge of the hood, as described in connection with Figure 5D. Optionally, the lumens of both probes 73A and 73 are used to provide a fluid input to the treatment area. For example, one of the probes supplies an ionized gas and the other supplies a fluid containing auxiliary species such as nitrogen, oxygen, and / or water molecules.

[0181] Referring to the method of Figure 6E in the context of Figures 6A - 6B, corresponding to block 610, in some embodiments, the target is localized using, for example, MRI imaging, CAT imaging, PET imaging, or another method.

[0182] Corresponding to block 612, in some embodiments, the plasma delivery tip 66 is guided through the introducer 605 into the region of the target 603 via a percutaneous incision (FIG. 6B), or via a catheter system, or acting as its own navigation device (FIG. 6A). The plasma delivery tip 66 optionally comprises a sharp end (e.g., a trocar or sharp point shape), or a non-invasive (non-wounding) end. The probe conduit 73 with the plasma delivery tip 66 is optionally steerable and optionally comprises a working channel for receiving a guide wire (or other tool), and / or is optionally inserted through the working channel of a catheter device or an endoscope.

[0183] Embodiments of the trocar tip are described, for example, in connection with FIGS. 2C, 3B, or 3F, and embodiments of sharp or non-invasive expandable tips are described, for example, in connection with FIGS. 5A - 5E. Optionally, a smooth tip plasma delivery tip 66 is used. The array for preparing the target region 603 is arbitrarily selected from the arrays depicted in connection with the target region 703.

[0184] Corresponding to block 614, in some embodiments, the use of an auxiliary scavenging lumen is optional. In some embodiments, scavenging is not required (e.g., the gas escapes through the bronchi and trachea). Optionally, the probe conduit 73 itself is provided with one or more gas scavenging lumens. When used, the auxiliary scavenging lumen can be introduced by any suitable means. Optionally, the distal end of a standard catheter system is introduced in the vicinity of the target 603 and is used to passively vent the ionized gas (as a pressure at the treatment site, passing the gas through) and / or to exhaust under negative pressure.

[0185] Corresponding to block 616, in some embodiments, the region of target 603 is treated with plasma. Liquid removal may or may not be an issue, depending on the condition of the lung and the location of target 603. Some examples of how the plasma delivery tip 66 can be moved during treatment are described in connection with FIG. 7, which also applies as an option available in the examples of FIGS. 6A-6B.

[0186] Referring now to FIGS. 7A-7C, which schematically depict the application of plasma treatment to a target 703 within a solid organ 704, according to some embodiments of the present disclosure. In FIG. 7A, a probe 73 is shown inserted into the region of a target 703 within a solid organ 74 (e.g., the liver). In the example of FIG. 7A, the plasma delivery tip 66 comprises an expandable distal end. In FIG. 7B, one or more probes 73C are introduced at different angles (simultaneously or at different times) to enable treatment of different regions of the target 703. In FIG. 7C, plasma is generated using a probe 73D that comprises a discharge electrode assembly 306 disposed with an ionized gas delivered by a second probe 73E. Using multiple probes, the functions of ionized gas delivery, power delivery (ionization), and ionized gas ventilation can be arbitrarily performed by any given probe in any given combination, e.g., gas delivery and gas ventilation, gas delivery and ionization, and / or gas ventilation and ionization (with at least the remaining function being handled by another one of the multiple probes). These three functions are arbitrarily divided among the three probes, with each probe handling one of the functions. The functions can also be replicated, e.g., multiple probes perform any one of the functions of gas delivery and gas ventilation, gas delivery and ionization, and / or gas ventilation and ionization. Optionally, auxiliary species are provided by the probe, either in combination with or separately from any one of the other three functions simply named.

[0187] Optionally, a target on the outer surface of a solid organ and / or on the surface between the leaves of a solid organ is targeted. The target includes, for example, a tumor region, or a region of pathogenic infection (e.g., bacteria, virus, and / or fungus).

[0188] Referring to the method of FIG. 6E in the context of FIGS. 7A-7C, corresponding to block 610, the target is localized using, for example, MRI imaging, CAT imaging, PET imaging, or another method.

[0189] Corresponding to block 612, the plasma delivery tip 66 and / or other probes 73C-73E are guided to the target region through the introducer 705 via a percutaneous incision. Optionally, the organ itself is penetrated using standard devices such as needles and / or trocars. Optionally, an embodiment of the sharp tip of the plasma delivery tip 66, for example, a trocar tip embodiment as described in connection with FIGS. 2C, 3B, or 3F, or an expandable embodiment of the sharp tip, for example, a version of the embodiment of FIG. 5E having a sharp and rigid calyx 510, is used. Optionally, the target 703 is prepared for plasma treatment by an incision or other partial incision, which potentially increases the surface area exposed to the plasma and / or loosens the treatment area to allow for greater expansion of the plasma delivery tip.

[0190] Corresponding to block 614, for an operation within the peritoneal cavity (which is typically ventilated anyway), a separate gas scavenging lumen is optionally omitted. However, in the case of a deeply embedded target 703, the ionized gas used to generate the plasma may tend to inflate and / or destabilize the working area. For this or another reason, a gas scavenging lumen can be inserted at the location where the ionized gas used to generate the plasma is recovered.

[0191] In response to block 616, plasma is actually generated and delivered. This delivery may be accompanied by an expansion of the plasma delivery tip 66 (to the extent that the expansion is permitted by spatial constraints) and / or may be performed later. Optionally, plasma delivery is performed with the tip 66 pressed against a portion of the target 703, utilizing the ante-chamber 20 to create a liquid-free region. Optionally, the tip 66 is inserted into a "pocket" from which liquid is flushed (e.g., by an ionized gas), enabling delivery of plasma from a position several millimeters away from the tissue surface. As the plasma delivery tip 66 is gradually inserted into the target (i.e., inserted, expanded, manipulated, folded, inserted slightly deeper, repeated), plasma is optionally delivered in several activation sequences along a track extending through the target 703. Additionally or alternatively, plasma delivery is performed during withdrawal of the plasma delivery tip. A sufficiently large target 703 is optionally plasma-treated in multiple passes, for example, along multiple insertion tracks passing through the target area. Optionally or alternatively, the treatment is applied superficially to the surface of the target area and / or a surface overlying a shallowly located target area, enabling scanning of the plasma delivery tip 66 on the surface.

[0192] Referring now to FIGS. 8A-8B, which schematically depict the application of plasma treatment to a target in the urinary tract, according to some embodiments of the present disclosure. FIG. 8A shows a treatment using a rigid cystoscope 810 inserted along the urethra 805, and FIG. 8B shows a treatment using a flexible cystoscope 901 inserted along the urethra 805.

[0193] Referring now to the method of FIG. 6E in the context of FIGS. 8A-8B, in response to block 610, the target is positioned endoscopically, for example, using a cystoscope.

[0194] Corresponding to block 612, in some embodiments, the plasma delivery tip 66 is guided through the urethra, through the cystoscopes 810, 901, to the target area. The plasma delivery tip 66 optionally has a blunt tip or a tapered non-invasive end. In some embodiments, the treatment targets 803, 803B are located on the inner wall of the bladder 801, where they are directly exposed to the plasma plume 10 generated from the plasma delivery tip 66. Optionally, the flexible cystoscope (at position 901B) is steered to the bladder inlet of the ureter 802, from where the plasma delivery tip 66 is guided to a target 803C located deeper within the urinary tract.

[0195] Corresponding to block 614, in some embodiments, the use of an auxiliary scavenging lumen is optional. When used, the auxiliary scavenging lumen can be introduced by any suitable means. Optionally, gas scavenging is performed through a separate channel of the cystoscopes 805, 901 that is also used to introduce the plasma delivery tip 66. Optionally, a dedicated gas scavenging device is introduced, for example, through another working channel of the cystoscopes 805, 901. Optionally, the plasma delivery tip 66 itself is provided with one or more gas scavenging lumens.

[0196] As corresponding to block 616, in some embodiments, the targets 803, 803B, 803C are treated with plasma. Even if the bladder 801 itself is substantially empty, a liquid evacuation capability within the plasma delivery tip 66 is preferred to prevent contamination from residual liquids. Liquids may also be encountered in the ureter 802 and should be evacuated. Some examples of how the plasma delivery tip 66 can be moved during treatment are described in connection with FIG. 7 and also apply as options available in the examples of FIGS. 8A-8B.

[0197] Next, refer to FIG. 9, which is a schematic flowchart of a method for delivering plasma to a target within a body lumen according to some embodiments of the present disclosure.

[0198] In block 910, in some embodiments, the distal side of the plasma delivery tip is pressed against a target selected for plasma treatment.

[0199] In block 912, in some embodiments, the distal portion of the plasma delivery tip is expanded by applying pressure from an ionized gas supplied to the plasma delivery tip that optionally inflates the plasma delivery tip.

[0200] In block 914, in some embodiments, plasma is delivered.

[0201] Next, refer to FIG. 10, which is a schematic flowchart of a method for delivering plasma to a target within a body lumen according to some embodiments of the present disclosure.

[0202] In block 1010, in some embodiments, the distal side of the plasma delivery tip is pressed against a target selected for plasma treatment.

[0203] In block 1012, in some embodiments, the valve of the plasma delivery tip is opened. The valve is configured to protect at least the plasma generating element of the plasma delivery tip (e.g., the luminal surface along the discharge electrode of the plasma delivery tip) from contamination.

[0204] In block 1014, in some embodiments, plasma is delivered.

[0205] Now, refer to FIG. 11, which is a schematic flowchart of a method for delivering a plasma-activated fluid to a target surface within a body lumen according to some embodiments of the present disclosure.

[0206] In block 1102, in some embodiments, a plasma plume is directed onto an environmental fluid within a body lumen. Optionally, the environmental fluid includes an aqueous liquid. Optionally, the environmental fluid includes a film of aqueous liquid (e.g., having a thickness of about 1 mm or less) disposed between the target surface and a layer of gaseous fluid. In some embodiments, the movement of the liquid of the film relative to the surface is governed by surface interactions such as surface tension, cohesive forces, van der Waals forces, and / or Plateau–Rayleigh instabilities. Optionally, the aqueous liquid film includes an aqueous layer covering the surface of the bladder or stomach, and / or another organ of the GI tract or urinary tract. The surface can be the luminal surface of an organ, the outer surface of an organ (e.g., the surface of an abdominal organ accessed laparoscopically), and / or a tissue surface created by an incision, cut, injection, or another surgical procedure.

[0207] Optionally, the environmental fluid includes an aqueous fluid of a greater thickness covering the target surface, e.g., a thickness greater than 1 mm, and / or a thickness large enough for the fluid to flow under a pressure (e.g., gravity) that does not primarily depend on surface interactions.

[0208] Optionally, the environmental fluid includes existing and / or naturally occurring body fluids and / or gases. Optionally, the environmental fluid includes liquids and / or gases that are artificially introduced into the region of the target surface, e.g., via an introduced delivery lumen. Optionally, the introduced delivery lumen is part of a plasma generation device that generates the plasma plume.

[0209] In block 1104, in some embodiments, an activation fluid is redistributed across the target surface. In some embodiments, the redistribution is facilitated by one or more of the following actions performed during and / or prior to block 1104: · Additional fluid is supplied near the fluid activation site, pushing the activated fluid outward from the fluid activation site. The fluid is optionally supplied using the lumen of the plasma delivery device (optionally, the gas delivery lumen used to deliver the ionized gas), the auxiliary lumen of the plasma delivery device, and / or the lumen of another device. The activated fluid and the fluid used for redistribution are optionally of the same or different composition. In some embodiments, the additional fluid is supplied over a period of minutes (e.g., 10 minutes) to hours or days (e.g., 1 week or more). · The area surrounding the fluid activation site is pre-dried and can more readily receive (e.g., "sponge up") the activated fluid spreading from the fluid activation site. Optionally, the drying is performed by using gas from the gas delivery lumen that also delivers the gas used to generate the plasma, the auxiliary lumen of the plasma delivery device, and / or the lumen of another device. · The activated fluid is agitated, for example, by directing jets of gas and / or liquid into the area of the activated fluid. Optionally, the jets are provided from the gas delivery lumen that also delivers the gas used to generate the plasma (which may include the plasma plume itself). Optionally, the agitation is performed using the auxiliary lumen of the plasma delivery device and / or the lumen of another device.

[0210] Refer to FIG. 12, which is a schematic flowchart of a method for delivering a plasma-activated fluid to an inaccessible target surface within a body lumen, according to some embodiments of the present disclosure.

[0211] In block 1202, in some embodiments, a target surface that is not accessible to direct impingement by the plasma plume from the plasma treatment device is selected.

[0212] In block 1204, in some embodiments, the plasma is directed from the plasma processing device onto a portion of a fluid (optionally, an aqueous fluid) that is in contact with the target surface. In some embodiments, the fluid comprises saline. In some embodiments, the fluid comprises a noble gas.

[0213] In block 1206, in some embodiments, the activation fluid is redistributed so as to reach the target surface. Optionally, the activation fluid is actively redistributed using, for example, one of the operations described in connection with block 1104 of FIG. 11.

[0214] In some lung disease treatments (e.g., severe cases of pneumonia), the patient's lungs are flushed with saline, for example, to help remove mucus. Optionally, plasma generation is performed within the lungs using a plasma delivery tip that generates plasma directly on the saline. Optionally, the outlet opening of the plasma delivery tip is intentionally immersed in the saline and operated within the saline.

[0215] In some lung disease treatments, the patient's lungs are treated by inflating them with oxygenated helium gas (e.g., by avoiding the introduction of pressurized nitrogen) due to alveolar occlusion conditions (e.g., severe pneumonia). In some embodiments, plasma is generated within the oxygenated helium gas mixture. Thus, the helium gas mixture serves as an environmental fluid that becomes the activation fluid and enables the distribution of reactive species induced into the activation fluid by the plasma.

[0216] In some embodiments, the activating fluid in the body contains, for example, an amount of at least 100 ml, 500 ml, or 1000 ml. The amount of fluid is optionally, for example, maintained by maintaining liquid infusion and / or is periodically flashed and / or refreshed. The activation of the fluid is optionally carried out continuously, for example, over several minutes (e.g., 10 minutes), several hours (e.g., 10 hours), or several days. By continuous activation, a long-term exposure of the treatment target to plasma-induced reactive species is obtained. Optionally, once positioned, the plasma delivery device is operated without the need for continuous active navigation or other direct supervision. Optionally, the plasma delivery tip of the plasma delivery device is placed at a convenient in-body location in fluid communication with the treatment target, but is not inserted too deeply into the body cavity so as to prevent it from staying in a predetermined position for a long time without a certain direct monitoring.

[0217] The distance between the plasma delivery tip and the target surface to be treated is optionally separated by several centimeters, for example, at least 3 cm, 4 cm, 5 cm, 10 cm, or another distance, by the activating fluid.

[0218] In some embodiments, for example, the bladder or other hollow organ is treated by maintaining it filled with a few milliliters of liquid (e.g., at least 50 ml of fluid), in which reactive species are continuously induced by the operation of the plasma delivery tip of the plasma treatment device.

[0219] Plasma treatment in a liquid-filled lumen Reference is made to FIGS. 13A - 13B, which schematically depict plasma delivery tips 1301, 1351 that operate to deliver plasma to a target 1323 positioned within a lumen space 1310 established by the inflation of balloons 1303A - 1303D, according to some embodiments of the present disclosure. Reference is also made to FIG. 13C, which is a schematic flowchart of a method of using the plasma delivery tips 1301, 1351 of FIGS. 13A - 13B, according to some embodiments of the present disclosure.

[0220] In block 1371 (FIG. 13C), one of the plasma delivery tips 1301, 1351 is inserted into the body lumen wall 1321, which can be, for example, the lumen wall of a blood vessel, the intestine (e.g., the colon), or the lumen of the urinary tract.

[0221] In block 1372, in some embodiments, balloons 1303A - 1303B, 1303C - 1303D expand to seal the lumen space 1310.

[0222] In the example of FIG. 13A, balloon 1303A is a toroidal balloon, delivered around the cylinder 1302 of the probe tip 1301 and inflated in that position to make a seal with the lumen wall 1321. Balloon 1303B is optionally inflated distally to the distal end of the plasma delivery tip 1301 using a separate device or, as shown, after the distal advancement of the inflation member 1305 that carries balloon 1303B out of the storage compartment 1307.

[0223] The balloons 1303C - 1303D of FIG. 13B are also toroidal balloons, each standing on the cylinder 1349 of the plasma delivery tip 1351. The cylinder 1349 also has one or more openings 1341, 1342 through which fluid is transported into and / or out of the lumen space 1310 and from / to the fluid conduits 1352, 1353. The openings 1341, 1342 are located on the cylinder 1349 between the two balloons 1303C, 1303D.

[0224] After sealing the lumen space 1310, in block 1373, in some embodiments, the fluid 1325 that initially filled the lumen space 1310 is drained, for example, by suction through the fluid conduits 1311, 1353, and fluid is supplied to replace the fluid drained through the fluid conduits 1312, 1352. Additionally or alternatively, a wash of gas and / or liquid through the liquid conduits 1312, 1352 pushes the existing fluid within the lumen space 1310 out through the fluid conduits 1311, 1353.

[0225] The drainage optionally includes a washing step (using a liquid such as water and / or saline) followed by a purge step using a gas. Optionally, it is a drying gas to assist in removing residual moisture.

[0226] Once the lumen space 1310 is sufficiently cleared, in some embodiments, at block 1374, plasma generation is initiated by delivering a voltage to electrode 306 via electrical conduit 1304 (FIG. 13A) or to electrode 1353 via electrical conduit 1354 (FIG. 13B). The lumen space 1310 is optionally translated along the lumen wall 1321 by advancing and / or retracting the plasma delivery chips 1301, 1351. This potentially provides coverage over a larger area and / or allows for correction if the initially established lumen space 1310 is partially off-target.

[0227] The ionized gas is carried into the lumen space 1310 via fluid conduits 1312, 1352 and returned via fluid conduits 1311, 1353.

[0228] The generated plasma diffuses within the lumen space 1310, potentially reaching all locations, particularly the location of target 1323 which may include tissue abnormalities targeted for plasma treatment.

[0229] After the treatment is complete, at block 1375, in some embodiments, the gas is removed, optionally after being replaced again with a liquid (e.g., saline) and before deflating balloons 1303A - 1303B (at block 1376).

[0230] General As used herein with respect to amounts or numerical values, the term "about" refers to ±10%.

[0231] The terms "comprises", "comprising", "includes", "including", "having", and their conjugates mean "including but not limited to".

[0232] The term "consisting of" means "including and limited to".

[0233] The expression "consisting essentially of" means that a composition or method may include additional ingredients and / or steps, but only to the extent that the additional ingredients and / or steps do not substantially change the basic and novel characteristics of the composition or method recited in the claims.

[0234] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" can include a plurality of compounds including mixtures thereof.

[0235] As used herein, the term "exemplary" is used in the sense of "providing an example, instance, or illustration". Any embodiment described as "example" or "exemplary" need not be construed as preferred or advantageous over other embodiments, and / or need not be construed as excluding the incorporation of features from other embodiments.

[0236] As used herein, the term "optionally" is used in the sense of "provided in some embodiments and not provided in other embodiments". Any particular embodiment of the present disclosure may include a plurality of "optional" features so long as such features are not inconsistent.

[0237] As used herein, the term "method" refers to methods, means, techniques, and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques, and procedures known to, or readily developed from, methods, means, techniques, and procedures known to physicians in the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0238] As used herein, the term "treating" includes arresting, substantially inhibiting, delaying, or reversing the progression of a condition, substantially improving the clinical or aesthetic symptoms of a condition, or substantially preventing the appearance of the clinical or aesthetic symptoms of a condition.

[0239] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, a description of a range should be considered to have specifically disclosed all the individual numerical values and all sub-ranges within that range. For example, a range description such as from 1 to 6 should be considered to specifically disclose sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as the individual numerical values within that range, for example, 1, 2, 3, 4, 5, 6, etc. This applies regardless of the breadth of the range.

[0240] Whenever a numerical range (e.g., "10 to 15", "10 - 15", or any number of pairs linked by another such range indication) is shown in this specification, unless the context clearly indicates otherwise, it is meant to include any numerical value (fractional or integer) cited within the indicated range. In this specification, the expressions "range between" a first display number and a second display number, and "range from" a first display number "to" a second display number (or another such term indicating a range) are used interchangeably and are meant to include the first and second display numbers, and all fractional and integer numbers therebetween.

[0241] Although the invention has been described in connection with its specific embodiments, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the invention is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0242] For clarity, it is understood that specific features of the invention described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may be provided separately, or in any suitable sub - combination, or as appropriate in other described embodiments of the invention. Specific features described in the context of various embodiments are not considered essential features of those embodiments, unless the embodiments would not operate without those elements.

[0243] All publications, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. Further, the citation or identification of a reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not necessarily be construed as limiting. Also, the priority documents of this application are hereby incorporated by reference in their entirety.

Claims

1. A plasma delivery tip for a medical grade plasma generation device, wherein the medical grade plasma generation device is configured for in vivo delivery of the plasma delivery tip via a working channel, a gas delivery lumen defined within a peripheral wall, having a proximal-distal axis along which a flow of ionized gas flows to a distal opening of the gas delivery lumen, and a discharge electrode separated from the flow by a dielectric barrier and configured to transmit a high voltage to the flow of ionized gas when attached to a high voltage source, a one-way valve disposed between the discharge electrode and the distal opening to prevent proximal ingress of contamination into the longitudinal position of the discharge electrode along the proximal-distal axis, thereby preventing liquid contamination in the plasma generation region of the plasma delivery tip. A plasma delivery tip for a medical grade plasma generation device, comprising a one-way valve.

2. The plasma delivery tip according to claim 1, wherein the one-way valve is also arranged to prevent ingress of liquid material through the distal opening when closed.

3. The plasma delivery tip according to claim 1 or 2, wherein the plasma delivery tip comprises an expandable distal portion terminating at the distal opening, the expandable portion being configured to expand in diameter to increase a treatment area simultaneously treatable by an emitted plasma plume.

4. The plasma delivery tip according to any one of claims 1 to 3, wherein the one-way valve opens under pressure from the flow of ionized gas.

5. The plasma delivery tip according to any one of claims 1 to 3, wherein the one-way valve comprises an actuating valve actuated separately from the pressure from the flow of ionized gas.

6. The plasma delivery tip according to any one of claims 1 to 5, wherein the distal opening of the gas delivery lumen is angled obliquely with respect to the proximal-distal axis.

7. The plasma delivery tip according to any one of claims 1 to 5, wherein the one-way valve comprises a leaf valve, a slit valve, or a flap valve.

8. The plasma delivery tip according to any one of claims 1 to 7, wherein the one-way valve is configured to deflect a plasma plume generated within the flow of ionized gas by the high voltage pulse to an angle varying according to the opening degree of the one-way valve.

9. A plasma delivery tip according to any one of claims 1 to 8, comprising an outer peripheral wall surrounding the peripheral wall of the gas delivery lumen and radially spaced from the peripheral wall to define a gap through which the ionized gas is scavenged after delivery to the discharge electrode.

10. A plasma delivery tip according to any one of claims 1 to 8, wherein the peripheral wall of the gas delivery lumen also defines a conduit through which the ionized gas is scavenged after delivery to the discharge electrode.

11. The expandable portion comprises an ante-chamber arranged along the proximal-distal axis between the discharge electrode and the distal opening, according to claim 3 of the plasma delivery tip.

12. The ante-chamber expands to have an inner diameter at least 1.5 times larger than the inner diameter of the ante-chamber in the folded configuration, according to claim 11 of the plasma delivery tip.

13. The one-way valve comprises a calyx, the calyx having one or more leaves attached to the outside of the plasma delivery tip proximal to the calyx, according to any one of claims 2 and 11 to 12 of the plasma delivery tip.

14. The leaves are split from each other when expanded to expose the distal opening of the gas delivery lumen, according to claim 13 of the plasma delivery tip.

15. The expanded ante-chamber defines the distal opening of the gas delivery lumen on the distal side of the ante-chamber, according to claim 12 of the plasma delivery tip.

16. The folded configuration of the ante-chamber comprises a rigid and sharp tip configured to penetrate tissue, according to any one of claims 11 to 12 and 15 of the plasma delivery tip.

17. The discharge electrode extends around at least a portion of the periphery of the gas delivery lumen, according to any one of claims 1 to 16 of the plasma delivery tip.

18. The discharge electrode is arranged with the gas delivery lumen and surrounded by the flow of the ionized gas, according to any one of claims 1 to 16 of the plasma delivery tip.

19. The outer diameter of the plasma delivery tip is less than 5 mm, according to any one of claims 1 to 18 of the plasma delivery tip.

20. The distal portion of the peripheral wall distal to the discharge electrode is foldable, according to claim 12 of the plasma delivery tip.

21. The plasma delivery tip according to claim 12 or 20, wherein the peripheral wall comprises a thinner wall portion distal to the discharge electrode and a thicker wall portion within the plasma generation region.

22. The plasma delivery tip according to claim 21, wherein the thinner wall portion and the thicker wall portion are fixed relative to each other along the proximal-distal axis.

23. The plasma delivery tip according to claim 21, wherein the thinner wall portion and the thicker wall portion are movable relative to each other along the proximal-distal axis through a maximum relative displacement of 50 mm or less.

24. A probe having a plasma delivery tip according to any one of claims 1 to 23, sized for insertion into a selected portion of a body lumen, and a plurality of balloons passing through at least one through which the probe extends, wherein the plurality of balloons are sized and arranged to expand within a selected portion of the body lumen, seal an opening therebetween, define a lumen space therebetween, A medical-grade plasma generation device, wherein the distal tip of the probe including the discharge electrode is configured to be disposed between the plurality of balloons within the lumen space such that at least a first balloon is disposed proximal to the opening and at least a second balloon is disposed distal to the opening, and plasma is generated therein.

25. The plasma generation device according to claim 24, wherein the balloon is sized to seal a portion of a blood vessel lumen or is sized to seal a portion of an intestinal lumen.

26. A probe having a plasma delivery tip according to any one of claims 1 to 23, sized for insertion into a selected portion of a body lumen, and a switching valve operable to switch between delivering the ionized gas into the lumen of the probe and delivering another second fluid into the lumen of the probe, wherein the second fluid is delivered from the lumen of the probe into the ambient fluid surrounding it, A medical-grade plasma generation device comprising a controller configured to control the switching valve to have a duty cycle for the switching of the delivery.

27. The one-way valve according to claim 17, which is configured to leave a clear opening through which the plasma plume passes when open and not to restrict the plasma plume.

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