Systems and methods for delivering a combination therapeutic effect

Abstract

Systems and methods are disclosed for providing a therapeutic effect to biological tissue of plasma in combination with a pharmaceutical or biologic drug agent. The systems include a console configured to be coupled to a power source and configured to be coupled to a supply of gas and a treatment head or handpiece configured to receive a drag agent cartridge, the treatment head or handpiece being connectable to the console and including a plasma generation chamber.

Description

[0001] Docket No. A2246-7000WO

[0002] SYSTEMS AND METHODS FOR DELIVERING A COMBINATION THERAPEUTIC EFFECT

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Ser. No. 63 / 756,211, filed on February 9, 2025. titled “SYSTEMS AND METHODS FOR DELIVERING A COMBINATION THERAPEUTIC EFFECT”, which is incorporated herein by reference in its entirety for all purposes.

[0004] FIELD OF TECHNOLOGY

[0005] Aspects and embodiments disclosed herein are generally related to systems and methods for delivering a therapeutic effect to biological tissue from a plasma source in combination with a pharmaceutical or biologic agent. More specifically, aspects and embodiments disclosed herein relate to systems and methods for simultaneous delivery of cold atmospheric pressure plasma and a pharmaceutical or biologic agent.

[0006] SUMMARY

[0007] In accordance with one aspect, there is provided a delivery device for topically applying a mixed stream of an atmospheric pressure plasma jet (APPJ) and drug agent. The delivery device may comprise a console configured to be coupled to a power source and configured to be coupled to a supply of gas. The delivery device may comprise a treatment head configured to receive a drug agent cartridge, the treatment head comprising a plasma generation chamber configured to be fluidly connected to the supply of gas and a mixing chamber fluidly connected to the plasma generation chamber and configured to receive the drug agent from the drug agent cartridge, the plasma generation chamber comprising an anode electrode and a cathode electrode electrically connectable to the power source, the treatment head being configured to direct the mixed stream toward a target tissue. The delivery device may comprise a spacer attachment removable attachable to the treatment head.

[0008] The treatment head of the delivery device may be further configured to receive the removable attachable drug cartridge.Docket No. A2246-7000WO

[0009] The delivery device may comprise the mixing chamber positioned upstream of the plasma generation chamber such that the mixing chamber is configured to fluidly connect a flow of gas from the supply of gas with a drug agent received from the drug agent cartridge upstream from the plasma generation chamber.

[0010] The delivery device may comprise the mixing chamber positioned within the plasma generation chamber, such that the mixing chamber is configured to fluidly connect a flow of gas from the supply of gas with a drug agent received from the drug agent cartridge between the cathode and anode electrodes.

[0011] The delivery device may comprise the mixing chamber positioned downstream of the plasma generation chamber and configured to be positioned downstream of the drug agent cartridge.

[0012] The delivery device may comprise one or both of the anode electrode and the cathode electrode comprising a ring electrode positioned around the plasma generation chamber.

[0013] In some embodiments, the cathode electrode may comprise a ring electrode positioned around the plasma generation chamber and the anode electrode may comprise a rod electrode positioned within the plasma generation chamber.

[0014] In some embodiments, the anode electrode may comprise a ring electrode positioned around the plasma generation chamber and the cathode electrode may comprise a rod electrode positioned within the plasma generation chamber.

[0015] The delivery device may comprise a source of ultraviolet light.

[0016] The delivery device may comprise a spacer attachment that comprises one or more boundary walls that maintain a substantially constant cross-sectional area of the mixed stream while being directed toward the target tissue.

[0017] The delivery device may comprise a spacer attachment that comprises one or more inwardly angled boundary walls that gradually reduce a cross-sectional area of the mixed stream while being directed toward the target tissue.

[0018] The delivery device may comprise an opening at a distal end of the spacer attachment that is substantially unobstructed.

[0019] The delivery device may comprise a cross-section of a distal end of the spacer attachment that comprises a mechanical reticle.Docket No. A2246-7000WO

[0020] The delivery device may comprise a distal end of the spacer attachment that comprises a membrane.

[0021] In some embodiments, the membrane is configured to be loaded with a drug or biological agent.

[0022] The delivery device may comprise a spacer attachment that comprises an electrical connection configured to maintain a voltage potential on a lateral and / or distal surface of the spacer attachment.

[0023] In accordance with another aspect, there is provided a delivery device for topically applying a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent. The delivery device may comprise a console configured to be coupled to a power source and configured to be coupled to a supply of gas, the console being electrically connected to a control system configured to control delivery of the mixed stream in an amount effective to produce a therapeutic effect at a target tissue. The delivery device may comprise a treatment head configured to receive a drug agent cartridge, the treatment head comprising a plasma generation chamber configured to be fluidly connected to the supply of gas and a mixing chamber fluidly connected to the plasma generation chamber and configured to receive the drug agent from the drug agent cartridge, the plasma generation chamber comprising an anode electrode and a cathode electrode electrically connectable to the power source, the treatment head being configured to direct the mixed stream toward a target tissue.

[0024] The treatment head of the delivery device may further comprise a video camera system configured to capture visual images of a treatment zone.

[0025] In some embodiments, the control system may be programmed to execute an algorithm that identifies one or more areas of the target tissue that require treatment responsive to the visual images of the treatment zone.

[0026] In accordance with another aspect, there is provided a delivery device for applying a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent. The delivery device may comprise a console configured to be coupled to a power source and configured to be coupled to a supply of gas. The delivery device may comprise a handpiece configured to receive a drug agent cartridge, the handpiece comprising a mixing chamber configured to be fluidly connected to the supply of gas and configured to receive the drug agent from the drug agent cartridge, and a connector fluidly connected to the mixing chamber. The delivery device may comprise an elongateDocket No. A2246-7000WO

[0027] catheter having an inner lumen fluidly connected to the connector and configured to receive a mixture of the gas and the drug agent from the mixing chamber. The elongate catheter may comprise a plasma generation chamber downstream from the inner lumen. The elongate catheter may comprise an anode ring electrode and a cathode ring electrode electrically connectable to the power source, the anode and cathode ring electrodes positioned around the plasma generation chamber. The elongate catheter may comprise a biocompatible sheath encapsulating the inner lumen and the anode and cathode ring electrodes.

[0028] The biocompatible sheath of the delivery device may comprise an expandable balloon. The delivery device may comprise a distal end of the elongate catheter dimensioned to allow delivery of the elongate catheter over a guidewire.

[0029] In accordance with another aspect, there is provided a method of treating infectious keratitis, keratoconus, or a wound in a subject, comprising administering to a target site of the infectious keratitis, keratoconus, or wound a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent in an amount effective to treat the infectious keratitis, keratoconus, or wound.

[0030] In some embodiments, the drug agent is a photosensitizing agent.

[0031] In some embodiments, the drug agent is selected from a list of drug agents known or approved for treatment of the infectious keratitis, keratoconus, or wound.

[0032] In some embodiments, the drug agent comprises one or more of riboflavin, methylene blue, toluidine blue, rose Bengal, curcumin, hypericin, phthalocyanines, porphyrins, zinc, fullerenes, and titanium dioxide.

[0033] In some embodiments, the target site comprises ocular tissue.

[0034] In some embodiments, the ocular tissue is affected by infectious keratitis.

[0035] In some embodiments, the ocular tissue is affected by keratoconus.

[0036] In some embodiments, the target site comprises a wound.

[0037] Ins some embodiments, the wound is a diabetic foot ulcer.

[0038] In accordance with another aspect, there is provided a method of administering a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent to a subject, the method comprising: providing a delivery device, the delivery device comprising: a console configured to be coupled to a power source and configured to be coupled to a supply of gas; a treatment head configured to receive a drug agent cartridge, the treatment head comprising a plasma generationDocket No. A2246-7000WO

[0039] chamber configured to be fluidly connected to the supply of gas and a mixing chamber fluidly connected to the plasma generation chamber and configured to receive the drug agent from the drug agent cartridge, the plasma generation chamber comprising an anode electrode and a cathode electrode electrically connectable to the power source, the treatment head being configured to direct the mixed stream toward a target tissue; providing instructions to electrically connect the delivery device to the power source and fluidly connect the delivery device to the supply of gas; providing instructions to load the drug agent cartridge into the delivery device; and providing instructions for operation of the delivery device to administer the mixed stream of APPJ and drug agent to a target site of the subject.

[0040] The method may further comprise providing the supply of gas, wherein the supply of gas is selected from a noble gas or a combination of noble gasses.

[0041] The method may further comprise providing the drug agent cartridge.

[0042] The disclosure contemplates all combinations of any one or more of the foregoing aspects and / or embodiments, as well as combinations with any one or more of the embodiments set forth in the detailed description and any examples.

[0043] BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. In the drawings:

[0045] FIG. 1 is a schematic drawing of a delivery device comprising a console and treatment head for creating a mixed stream of APPJ and drug agent, according to one embodiment;

[0046] FIG. 2a is a schematic drawing of a treatment head, according to one embodiment;

[0047] FIG. 2b is a schematic drawing of a treatment head, according to one embodiment;

[0048] FIG. 3 is a schematic drawing of a treatment head, according to one embodiment;

[0049] FIG. 4 is a schematic drawing of a treatment head, according to one embodiment;

[0050] FIG. 5a is a schematic drawing of a handpiece including a cylindrical spacer attachment, according to one embodiment;

[0051] FIG. 5b is a schematic drawing of a handpiece including a tapered spacer attachment, according to one embodiment;Docket No. A2246-7000WO

[0052] FIG. 6 shows various example cross- sections of the distal tip of a spacer attachment, according to several embodiments;

[0053] FIG. 7 is a schematic drawing of an example handpiece and catheter configuration for treating luminal body structures, according to one embodiment.

[0054] DETAILED DESCRIPTION

[0055] Plasma is a state of matter formed from an ionized gas, in which the electrons from the gas molecules are dissociated from their respective protons and neutrons. Multiple types of plasma may be created by electrical devices, including hot or cold and low-pressure or atmospheric pressure plasmas. As disclosed herein, “hot” may refer to temperatures significantly higher than room temperature, “cold” may refer to temperatures at or near room temperature, “low-pressure” may refer to pressures near vacuum, and “atmospheric pressure” may refer to pressures at approximately the normal ambient environment.

[0056] The disclosure relates to the use of cold atmospheric pressure plasma for medical applications. While not wishing to be bound by theory, it is believed that cold atmospheric pressure plasma may provide beneficial effects in medical treatment since it generally does not cause thermal damage and may be created in a normal ambient pressure environment.

[0057] Cold atmospheric pressure plasmas may be created by various techniques, including dielectric barrier discharge (DBD), surface barrier discharge (SBD), or atmospheric pressure plasma jet (APPJ). Exemplary methods and devices for the creation of cold atmospheric pressure plasma are described in Kazemi et al., “Cold atmospheric plasma medicine: applications, challenges, and opportunities for predictive control,” Plasma 7. 8 pages. MDPI (Mar. 16, 2024), which is herein incorporated by reference in its entirety for all purposes.

[0058] APPJ devices use gas flow, typically in the form of one or more noble gasses, to create the plasma medium and provide directionality to the effect. When using predetermined gas mixtures at predetermined flow rates, APPJ devices may have the additional benefit of being largely immune from fluctuations in atmospheric conditions such as humidity, presence of contaminants, and airflow that may interfere with tightly controlled plasma generation.

[0059] APPJ may be used for several medical applications. For instance, a direct application of the plasma stream may create an antimicrobial effect from the flux of reactive oxygen and reactive nitrogen species (RONS) present in the plasma. Secondary therapeutic effects may be derived fromDocket No. A2246-7000WO

[0060] the application of one or more of UV light, electric field, and mild heat generation associated with the plasma. It is further envisioned that using a plasma source to inject long-lived RONS, such as hydrogen peroxide, within a fluid or hydrogel, may create a plasma activated medium (PAM) that may be delivered to a target tissue to induce antimicrobial effects. PAM may be created with a broad variety of plasma sources including DBD, SBD, and APPJ devices. The fluid or hydrogel may be simple, for example, including sterile water and / or saline solution.

[0061] The therapeutic effect of cold atmospheric pressure plasma or PAM is believed to arise from the physical characteristics of the plasma or the long-lifetime RONS residing in a PAM. The disclosure generally relates to systems and methods for medical treatment which employ the delivery of a pharmaceutical or biologic agent, also referred to as a drug agent herein, combined with the simultaneous delivery of a plasma stream, such as a cold atmospheric pressure plasma generated by an APPJ device. The combination of the two therapeutic elements is believed to provide mutually reinforcing effects for certain medial applications, including, for example, the treatment of various ophthalmic diseases and infections. Additional applications may include, but are not limited to, wound healing (e.g., diabetic ulcers and other slow healing wounds), biofilm, dentistry, cancer therapy, skin diseases, and vascular conditions. It is believed that in the treatment of such conditions the combined and synergistic delivery of a drug agent and plasma may provide unexpected, enhanced effects compared to the delivery of either element alone. The disclosure is generally directed to the selection of a drug agent and device configuration that are aligned to provide an enhanced therapeutic effect for treatment of a particular disease or condition.

[0062] The diseases or conditions treatable by the systems and methods disclosed herein include any disease or condition for which the application of RONS may provide a therapeutic action or effect against the underlying disease or condition or a symptom thereof. Exemplary diseases and conditions include, but are not limited to. an infection or contamination associated with one or more microbial, viral, fungal, or parasitic organism. The infection to be treated may be found in one or more of the skin, eyes, ears, oral cavity, nasal passages, upper and lower airways, gastrointestinal tract, brain, blood, and other organs. Cold atmospheric pressure plasma may be applied in an amount effective to treat infective diseases. For instance, infectious organisms sensitive to exposure to reactive species such as RONS may be weakened, impeded from being replicated, or killed after exposure to sufficient levels of RONS for a sufficient period of time.Docket No. A2246-7000WO

[0063] In other embodiments, the diseases or conditions treatable by the systems and methods disclosed herein include diseases or conditions that relate to the compromise of normal collagen structure and subsequent loss of biomechanical functionality. Cold atmospheric pressure plasma may be applied in an amount effective to improve cross-linking of collagen fibers in the target tissue to restore biomechanical functionality and prevent disease progression. In certain embodiments, the systems and methods disclosed herein may be employed for the treatment of weakened blood vessels which have led to aneurysm formation, for example, in the brain or aorta.

[0064] The systems and methods disclosed herein may include the combination of cold atmospheric pressure plasma with a drug agent. In some embodiments, the APPJ stream is mixed with a drug agent selected to enhance the overall therapeutic benefit for the medical application. For instance, in certain embodiments, the drug agent may be selected to produce a photosensitizing effect, so as to create radical oxygen species (ROS) when exposed to light wavelengths present in the APPJ, such as ultraviolet (UV) light.

[0065] While not wishing to be bound by theory, it is believed that application of a UV-sensitive photosensitizing drug agent with the APPJ effluent may provide additional ROS beyond what is native to the plasma. Furthermore, the drug agent molecules may be selected to absorb UV radiation during the process of ROS creation, lowering the resulting unwanted UV exposure. The amplification of ROS creation via absorption of UV light from the plasma by the drug agent molecules is believed to have the effect of increasing the overall stress on the infective organisms, thereby decreasing treatment time. Simultaneously, UV exposure may be reduced, further improving treatment safety. Thus, the embodiments disclosed herein may provide additional benefits for patient comfort and efficient clinical workflow.

[0066] Certain applications, such as treating weakened blood vessels, may be impossible with treatment times longer than tens of seconds or several minutes due to the need to occlude normal blood flow while delivering the treatment. The systems and methods disclosed herein may be applied for a selected amount of time that is compatible with treatment of the particular disease or condition, including treatments that must be performed for a short period of time, such as a period of less than several minutes or even less than tens of seconds. Furthermore, the systems and methods disclosed herein may allow the application of a unit dose of the therapy to be defined by delivery of a preset amount of drug agent, for example, equivalent to the contents of one drug cartridge or to a preset portion of a drug cartridge.Docket No. A2246-7000WO

[0067] It is further believed that the strong electric fields present in an APPJ may produce a temporary electroporation effect in biotissue, whereby tight junctions are opened, and permeability is increased during exposure to the plasma stream. Thus, in some embodiments, the combination of APPJ with administration of the drug agent may further improve delivery and penetration of the drug agent through biotissue to the target infectious organism. Furthermore, where the drug agent is selected to be a photosensitizer with strong UV absorption, the infectious organism may be put under further increased stress due to increased drug agent concentrations at the infection site during ROS generation. The ROS and RONS amplification effects achieved by certain embodiments of the systems and methods disclosed herein may have especially beneficial effects during treatment of rapidly progressive infections that, using current common methods in the art, require significant time to isolate the specific organism causing the infection so that an appropriate drug agent may be selected for treatment. ROS and RONS may generally provide broad-spectrum effects against infectious organisms and may therefore be applied regardless of the nature of the specific organism.

[0068] It is also possible to leverage the electroporation effect of the APPJ by substituting or augmenting the photosensitizing drug agent with an anti-microbial, anti-viral, anti-fungal, or anti-parasitic drug agent. Thus, in some embodiments, the drug agent may include an anti-microbial, anti-viral, anti-fungal, and / or anti-parasitic drug agent. In this way, the anti-infective effects of the RONS contained in the plasma stream may be combined with a second, complementary anti-infective mechanism from the drug agent. The combination may further improve permeability of the treatment, for example, when the drug agent has intrinsically poor transit through lipid barriers, such as, for example, those found in biofilms and epithelial tight junctions.

[0069] The benefits of a combined drug agent and APPJ delivery may have broad applications in treatment or prevention of infectious diseases in multiple tissue types and organ systems. Nonlimiting examples include treating demodex mite infestations in the eyelash follicles or skin to prevent disorders including blepharitis or rosacea, treating ear infections with particular benefit of the plasma stream reaching areas of the ear typically difficult to access with conventional liquid medications, and treating slow-healing wounds, such as diabetic ulcers, where mixed infections are common and extremely challenging to treat with pharmaceutical approaches. Furthermore, treatment with combined drug agent and APPJ delivery may limit or inhibit drug resistance when the primary mode of action is exposure to RONS.Docket No. A2246-7000WO

[0070] The benefits of a combined drug agent and APPJ delivery may also have broad applications in treatment or prevention of conditions found in luminal body organs, such as, for example, blood vessels and the gastrointestinal tract. For instance, the effects of strengthening tissue via crosslinking may be applied to treat or prevent life-threatening aneurysms in blood vessels including the neurovascular system or the aorta. In certain embodiments, the combined drug agent and plasma may be applied in an amount effective to strengthen the vessel tissue in and around a site of an aneurysm, which may preclude the need for a mechanical stent to be placed, reducing overall risk to the patient from the stent implantation procedure and from the chronic effects of permanently leaving a foreign body in the vessel. For blood vessel applications, the gas may be selected to prevent formation of bubbles in the blood stream. Thus, gas selection may take into consideration solubility of the gas within blood. In certain exemplary embodiments, carbon dioxide may be selected, for example, for its high solubility. The systems and methods disclosed herein may also be used for treatment of cancer where the cancerous cells are sensitive to RONS, which may occur in the epithelial tissues of luminal body structures, such as the gastrointestinal tract.

[0071] In one aspect, the disclosure relates to systems and methods for treating medical conditions where RONS and drug agents may interact and mutually reinforce each other to deliver an enhanced therapeutic effect relative to the delivery of one element alone. In some embodiments, the system may include a medical device comprising a console and a treatment head. The console may contain various electronics, control systems, user interfaces, and a gas supply. The console may be connected to the treatment head. The treatment head may include one or more structures for producing a mixed stream comprising the drug agent and APPJ. The mixed stream may be directed out from the treatment head toward the target tissue. While the specific examples used here relate to APPJ generation, it is well-understood that the same principles may also be applied to other types of plasma sources, including but not limited to DBD and SBD devices.

[0072] One exemplary system for creating a mixed stream of APPJ and drug agent that may be directed to a biological target tissue is shown in the schematic drawing of FIG. 1. The system comprises a console (106) that contains drive electronics. The console (106) may include or be connectable to a device running a control system, optionally operable by a user interface. The console (106) may be connectable to a supply of a gas (104), such as a gas tank or gas line. The console (106) may be configured as a portable medical cart. The system further comprises aDocket No. A2246-7000WO

[0073] treatment head (110) with appropriate structures for generation of an APPJ, mixing of the drug agent with the APPJ, and outwardly directing the mixed stream towards the target tissue (114).

[0074] A single- or multi-use cartridge (112) containing the drug agent may be removably attachable to the treatment head (110). The cartridge (112) may be attached to the treatment head (110) by the user. The structure for mixing the drug agent with the APPJ may be configured to mix the drug agent before, during, or after generation of the APPJ from the gas stream. A series of cables and conduits (108) may connect the console (106) and treatment head (110) for delivering electrical signals, data, and / or gas between the components. Treatment delivery may be initiated and halted by an actuator on the treatment head (110) or on the console (106). In exemplary embodiments, the actuator may be one or more of a button or switch on the treatment head (110) or on the console (106), or a foot pedal attached to the console (106).

[0075] A detailed, cross-sectional schematic diagram of one embodiment of the treatment head (110) is shown in FIG. 2a. In this exemplary embodiment, the drug agent cartridge (112) and gas supply (202) are fluidly connected to a mixing chamber (208), which is positioned to combine the drug agent from the drug cartridge (112) with the incoming gas supply (202) upstream from the plasma generation chamber (214). The drug agent may be provided in either a solid powder or liquid form. Mechanical or microfluidic elements may be positioned to direct a predetermined amount of the drug agent into the mixing chamber.

[0076] In some embodiments, the mixing chamber (208) may be integrated into the drug cartridge (112) itself such that the mixing chamber (208) is part of the single- or multi-use cartridge (112).

[0077] The embodiment shown in FIG. 2a further includes a single pair of an anode electrode (210) and cathode electrode (212) in the plasma generation chamber (214). The anode electrode (210) and cathode electrode (212), which may each independently be a ring electrode or a rod electrode, are configured to apply a high voltage across the plasma generation chamber (214). In certain embodiments, both the anode electrode (210) and the cathode electrode (212) are ring electrodes. In other embodiments, at least one of the anode electrode (210) and the cathode electrode (212) is a rod electrode, with the other being a ring electrode. In other embodiments, both the anode electrode (210) and the cathode electrode (212) are rod electrodes. Thus, in certain embodiments, the anode electrode (210) and cathode electrode (212) positions may be reversed compared to what is shown in FIG. 2a. Furthermore, in certain embodiments more than one pairDocket No. A2246-7000WO

[0078] of electrodes may be used rather than the single pair shown in the exemplary embodiment of FIG.

[0079] 2a.

[0080] The console may be electrically connectable to a power source (102). In certain embodiments, the power source may include a battery positioned in the console (106). Additionally or alternatively, the console (106) may be connectable to an external power source (102). The anode electrode (210) and cathode electrode (212) may be electrically connectable to the power source (102), optionally through the cables and conduits (108) that connect the console (106) to the treatment head (110). Voltage may be applied by the anode (210) and the cathode (212) as a radiofrequency (RF) signal at a voltage level effective to induce plasma formation in the selected gas stream (202).

[0081] While FIG. 2a shows the drug agent being mixed with the gas supply (202) upstream from the plasma generation chamber (214), in other embodiments the drug agent may be mixed with the gas supply (202) during plasma generation. This may be accomplished by injecting the drug agent from the drug cartridge (108) into the plasma generation chamber (214), for example, in between the anode electrode (210) and cathode electrode (212). Thus, in certain embodiments, the mixing chamber (208) may be positioned to combine the drug agent from the drug cartridge (108) with the incoming gas supply (202) within the plasma generation chamber (214).

[0082] An alternate embodiment of the treatment head is shown in FIG 3. In this embodiment, the drug agent may be mixed with the gas stream during plasma generation. For instance, the drug agent may be injected from the drug cartridge (112) between the anode electrode (210) and the cathode electrode (212). Thus, in certain embodiments, the mixing chamber (208) may be positioned within the plasma generation chamber (214).

[0083] In yet other embodiments, as shown in FIG. 4, the drug agent may be mixed with the plasma stream after plasma generation. For instance, the drug agent may be injected from the drug cartridge (112) downstream from the anode electrode (210) and the cathode electrode (212). Thus, in certain embodiments, the mixing chamber (208) may be positioned downstream from the plasma generation chamber (214). Mixing the drug agent with the plasma stream after plasma generation may be beneficial if the drug agent is sensitive to breakdown or other unwanted modification when exposed to high electric fields in the plasma generation chamber (214).

[0084] In certain embodiments, the drug agent or a liquid carrier of the drag agent may be converted into plasma by the plasma generation chamber (214). For instance, as the drug agent isDocket No. A2246-7000WO

[0085] mixed with the gas supply (202) and plasma is formed, the drug agent itself and / or the liquid used to dissolve the drug agent may become a plasma-activated medium that conveys additional therapeutic benefits when applied to the target tissue (114). Additionally, as the drug agent moves through the plasma generation chamber (214) and is integrated into the plasma, the drug agent may be exposed to UV light emitted from the plasma. The UV light exposure may trigger additional beneficial mechanisms in the drug agent, such as the creation of reactive oxygen species if the drug agent is a photosensitizer.

[0086] In certain embodiments, the system may include one or more direct sources of UV light (216), such as one or more light emitting diodes or lasers. The one or more sources of UV light (216) may be positioned to excite the drug agent upstream, within, or downstream from the plasma generation chamber (214). UV light may be provided in an amount effective to further augment the efficacy of the drug agent in response to absorption of UV photons.

[0087] An alternate embodiment of the treatment head (110) is shown in the schematic diagram of FIG. 2b. In the exemplary embodiment of FIG. 2b. the anode electrode (210) is a single rod electrode positioned within the plasma generation chamber (214) and the cathode electrode (212) is a ring electrode positioned around the plasma generation chamber (214). The cathode electrode (212) may include one or more ring electrodes positioned around the plasma generation chamber (214). In other embodiments, the cathode electrode (212) may be provided as a rod electrode within the plasma generation chamber (214) with one or more anode electrodes (210) positioned as ring electrodes around the plasma generation chamber (214). This design variation may be used to produce a different distribution of the electric field within the plasma generation chamber (214), which may be optimized differently than the dual ring electrode configuration of FIG. 2a to obtain desired plasma characteristics.

[0088] It is believed that the effects of a plasma stream on biological tissue may relate, in part, to the distance between the plasma generation source and the target tissue. It may be beneficial to maintain a fixed distance between the source plasma and the target tissue. The devices disclosed herein may comprise a spacer attachment dimensioned to provide a preselected fixed distance between the plasma generation chamber (214) and the target tissue during delivery of the plasma. Two exemplary embodiments of spacer attachments (502) that may be attached to the treatment head (110) are shown in FIG. 5a and FIG. 5b. The spacer attachment (502) may be a single- or multi-use spacer attachment (502).Docket No. A2246-7000WO

[0089] In certain embodiments, the spacer attachment (502) may be configured to maintain a substantially constant cross-sectional area of the mixed stream, as shown in FIG 5a. In other embodiments, the spacer attachment (502) may be configured to gradually reduce the cross-sectional area of the mixed stream, as shown in Figure 5b. The specific cross-sectional area of an opening of the spacer attachment (502) may be selected based on the medical application or target tissue. For example, for treatment of keratoconus. the size of the opening in the spacer attachment may be configured to be approximately the size of the cornea. Alternately, for treatment of emo ex-associated blepharitis, the size of the opening in the spacer attachment (502) may be configured to be approximately the size of an eyelash follicle or to be approximately the size of multiple follicles, for example as a slit opening.

[0090] In certain embodiments, the spacer attachment (502) may have solid walls so as to prevent ambient airflow around the target tissue (114) from interfering with delivery of the mixed stream. In certain embodiments, the spacer attachment (502) walls may be transparent to allow visualization of the target tissue (114) during treatment application.

[0091] The spacer attachment (502) may be further configured to provide additional therapeutic benefits depending on the specific medical application or target tissue, as shown in the exemplary embodiment of FIG. 6. One example in (A) of FIG. 6shows the opening at the distal tip of the spacer (602) may be substantially unobstructed to provide maximum flow through to the target tissue (114). In a second example in (B) of FIG. 6, the cross-section of the distal tip of the spacer (602) may include a mechanical reticle (604), to assist in precise targeting of a portion of target tissue (114). The mechanical reticle (604) may have a crosshair pattern, as shown in the exemplary embodiment of (B), or another pattern.

[0092] Another example in (C) of FIG. 6 shows the distal tip of the spacer attachment (602) may comprise a membrane (606). In exemplary embodiments, the membrane may extend across or partially cover a cross-section of the distal end of the spacer attachment. The membrane (606) may be loaded with a drug or biological agent. In certain examples, the membrane (606) may comprise a drug-loaded substrate or hydrogel. The drug or biological agent may be the same or different than the drug agent mixed with the plasma stream. In certain embodiments, the drug or biological agent may replace the drug agent mixed with the plasma stream. The chemical properties of the membrane (606) and drug or biological agent loaded within the membrane (606) may be selected to provide a timed or targeted release of the drug or biological agent. For instance, the drug orDocket No. A2246-7000WO

[0093] biological agent may be triggered to release upon contact with the target tissue (114). The chemical properties of the membrane (606) and drug or biological agent loaded within the membrane (606) may be selected such that the drug or biological agent is triggered to release upon exposure to the plasma stream or upon exposure to the mixed stream. In certain embodiments, the membrane (606) material may be configured to become a plasma-activated medium upon exposure to the plasma stream, thereby delivering its own additive therapeutic action to the target tissue (114).

[0094] The distal tip of the spacer attachment (602) may be designed or dimensioned to improve the spatial uniformity or achieve a desired spatial distribution of the mixed stream. In certain embodiments, the distal tip of the spacer attachment (602) may comprise an electrical connection (608) to the power source configured to maintain a voltage potential on a lateral and / or distal surface of the spacer attachment. Substantially the entire lateral surface of the spacer attachment (502) or just the distal end of the spacer attachment (602) may be held at a pre-selected voltage potential Vs relative to ground, as shown in the exemplary embodiment of (D) of FIG. 6. Since the plasma stream itself is highly charged, a relative charge on the spacer attachment (502) or distal tip of the spacer attachment (602) may be selected to attract or repel the mixed stream, thereby achieving a desired spatial distribution at the target tissue (114). The voltage potential, Vs, may be fixed as a DC signal or may vary with time as an AC signal.

[0095] The spacer attachment may include a visible light source for optically aligning the treatment head (110) to the target biological tissue (114) during use, as shown in the exemplary embodiment of (E) of FIG. 6. The visible light source, for example a laser, may be positioned to project a visible spotlight (610) on the mixed stream. The visible light source may be integrated into the spacer attachment (502) or into the treatment head (110). In some embodiments, the device may include multiple visible light sources positioned to provide a visible cue for lateral and axial positioning of the treatment head (110) during use. For example, the device may include an on-axis laser and an off-axis laser positioned to overlap at the desired treatment distance from the tip of the treatment head (110) to the target tissue (114). The lasers may be configured to emit line beams rather than collimated beams in order to provide additional clarity in positioning.

[0096] In certain embodiments, the treatment head (110) may include a video camera system (218) or other imaging system positioned to capture visual images of the target tissue (114) or treatment zone. The video camera system may be operably connectable to the console. A video stream mayDocket No. A2246-7000WO

[0097] be passed back to the console (106) via data connections (220) and live video may be displayed on a screen connected to or included on the console (106).

[0098] In certain embodiments, the console (106) and / or treatment head (110) may be electrically connected to a control system configured to control delivery of the mixed stream in an amount effective to produce a therapeutic effect at a target tissue (114). For instance, the console (106) and / or treatment head (110) may comprise one or more mechanical or microfluidic pumps or other injectors configured to control delivery of the supply of gas and / or drug agent. The control system may be operably connected to the mechanical or microfluidic pump(s) or other injector(s), and programmed to control delivery, optionally independently, of each of the supply of gas and drug agent. The control system may be a computer or mobile device.

[0099] In some embodiments, the control system may be configured to regulate one or more parameters to be at a fixed value or within a target range, and / or to provide for adjustment of one or more of the parameters either manually and / or by an automated algorithm. Such parameters may include, but are not limited to, a frequency and / or amplitude of the RF voltage passed to the electrodes, pulse duration of the RF voltage (if a pulsed field is desired), flow rate of the gas or gasses flowing from the console to the treatment head, or flow rate of the drug agent flowing from the drug agent cartridge to the mixing chamber. Thus, in certain embodiments, the control system may be electrically connectable to the anode electrode and cathode electrode and / or to the power source. The control system may be connectable to one or more flow meter or other sensor configured to measure flow rate of the gas or gasses and / or flow rate of the drug agent.

[0100] The control system may also be configured to halt treatment if certain conditions are met. Such conditions may include, but are not limited to, the desired treatment duration (time and / or dosage) being reached, the desired amount of drug being delivered (volume and / or mass), or a system fault or unsafe condition has been detected by the system. System faults or unsafe conditions may include, for example, an electrical fault, a software fault, an unsafe temperature within the system or at the treatment head, depletion of gas reserves and / or reduction below a target volume, depletion of drug reserves and / or reduction below a target volume, or an inability to reach or maintain the desired treatment parameters. Thus, in certain embodiments, the control system may be electrically connectable to the anode electrode and cathode electrode and / or to the power source. The control system may be connectable to one or more flow meter or other sensor configured to measure flow rate of the gas or gasses and / or flow rate of the drug agent. The controlDocket No. A2246-7000WO

[0101] system may be electrically connectable to one or more sensor configured to detect a fault or unsafe condition, such as a current, voltage, power, frequency, impedance, temperature, or other sensor. The control system may be programmed to halt treatment by cutting flow of the gas or gasses, flow of the drug agent, power to the electrodes, or a combination.

[0102] In some embodiments, a user interface may be connected to the control system and programmed to allow a user to view, input, select, and / or modify one or more parameters controlled by the control system. The user interface may also be configured to provide notifications and / or prompts to inform the user or guide user interaction in response to system status, detected system faults or unsafe conditions, or completion of a treatment. The user interface may be accessible on a screen connected to the console (106) or on a computer or mobile device connectable to the console (106).

[0103] In certain embodiments, the video camera system (106) may be connectable to the user interface. The user interface may be programmed to receive, and optionally stream, live video passed back to the console (106) by the video camera system (218). An artificial intelligence (Al) algorithm may be programmed to run on the user interface and / or control system. The Al algorithm may be responsive to visual images of the treatment zone, and may be configured to guide the user to areas of the target tissue (114) that require treatment or to indicate to the user when an area of the target tissue (114) has been sufficiently treated. The Al algorithm may run locally on the console (106) or on a networked computer system accessible to the console (106).

[0104] The exemplary treatment head configurations disclosed herein may be incorporated in a variety of devices for external or internal application, including, for example, topical and ophthalmic application devices (including, for example, a wand, a headset, and other devices), endoscope-style devices for treating luminal organs, arthroscopic devices, and / or end-effectors on robotic surgical systems. In certain embodiments, components of the treatment head may be configured as handpiece (702) and / or elongate catheter (706), described in more detail below. The systems and methods disclosed herein may be configured for a variety of medical applications including, for example, wound healing and / or mitigation of a microbial, viral, fungal, and / or parasitic infection, including treatment of biofilm, diabetic ulcers, ophthalmic wounds, and others, cancer treatment, or general open-field or arthroscopic surgical applications.

[0105] The components of the system disclosed herein may be arranged in alternate configurations to enable the treatment of luminal structures within the body. Exemplary luminal structures includeDocket No. A2246-7000WO

[0106] the gastrointestinal tract, blood vessels, and others. In such configurations, the system may further include an elongate catheter (706). As shown in the exemplary embodiment of FIG. 7, the drug agent cartridge (112) and the gas supply (202) may be fluidly connected to a mixing chamber (208) within a handpiece (702). The handpiece (702) may be configured for external use outside of the body. The handpiece (702) may be connectable to the elongate catheter (706) such that the mixture may be passed into the elongate catheter (706). that may be positionable inside the luminal body structure, either directly or through an introducer channel of a separate medical device, for example, an endoscope. The exemplary system of FIG. 7 may be used to produce a therapeutic effect in conjunction with an endoscopic surgical procedure, which may be performed manually or with a robotic system.

[0107] As shown in the exemplary embodiment of FIG. 7, in certain embodiments, the handpiece (702) may also comprise a connector (704) that is configured to mechanically and electrically connect to the elongate catheter (706). The elongate catheter (706) may comprise an inner lumen (708) that is configured to receive the mixture of gas and drag agent from the handpiece (702) via the connector (704).

[0108] In certain embodiments, plasma may be generated within the elongate catheter (706). As shown in FIG. 7, the elongate catheter (706) may comprise an anode electrode (210) and cathode electrode (212) for applying an electric field suitable for plasma generation, e.g., APPJ creation. The anode electrical connection (204) and cathode electrical connection (206) may route through the connector (704), connecting the anode electrode (210) and cathode electrode (212) to the power source.

[0109] The elongate catheter (706) may comprise a biocompatible sheath (710) encapsulating the anode electrode (210), cathode electrode (212), and inner lumen (708). The biocompatible sheath (708) may be formed of a material selected to substantially isolate the elongate catheter (706) components from bodily fluids.

[0110] In certain embodiments, the biocompatible sheath (710) may further comprise a tip to facilitate elongate catheter (706) delivery over a guidewire. In certain embodiments, the biocompatible sheath (710) may be configured as an expandable balloon. The balloon may be dimensioned to facilitate centration of the catheter within the target lumen, thereby providing a fixed preselected distance from the plasma generation source to the target tissue (114). Thus, inDocket No. A2246-7000WO

[0111] certain embodiments, the balloon may be dimensioned to facilitate centration of the catheter within a gastrointestinal tract, blood vessel, or other lumen.

[0112] The distal end of the elongate catheter (706) may be configured to direct the mixed stream coaxially with the elongate catheter (706), as shown in the exemplary embodiment of FIG. 7. In other embodiments, the distal end of the elongate catheter (706) may be configured to direct the mixed stream radially or at a preset angle relative to the elongate catheter (706) axis.

[0113] In accordance with another aspect, there is provided a method of producing a mixed stream of plasma and a drug agent. Also disclosed herein is a method of facilitating administration of a mixed stream of plasma and a drag agent. In certain embodiments, the methods may comprise facilitating treatment of a disease or condition disclosed herein, such as treatment of a wound, treatment or prevention of a microbial, viral, fungal, and / or parasitic infection, treatment of cancer, and / or treatment of a blood vessel that has led to aneurysm formation.

[0114] In accordance with another aspect, there is provided a method of treating a disease or condition disease or condition disclosed herein. Exemplary diseases or conditions include wound healing and / or mitigation of a microbial, viral, fungal, and / or parasitic infection, including treatment of biofilm, diabetic ulcers, ophthalmic wounds, and others, cancer treatment, or general open-field or arthroscopic surgical applications. The methods may comprise administering to a target site of the disease or condition a mixed stream of plasma and a drug agent in an amount effective to treat the disease or condition. The mixed stream of plasma and drug agent may be generated and / or administered with a delivery device for the mixed stream of plasma and a drug agent, as disclosed herein.

[0115] The mixed stream of plasma and a drug agent may be topically administered to a target tissue, such as an external target tissue, including a dermal tissue or an ophthalmic tissue. In other embodiments, the mixed stream of plasma and a drug agent may be administered to a luminal tissue of a subject, including a gastrointestinal tissue or a blood vessel.

[0116] The methods may comprise providing a delivery device for the mixed stream of plasma and a drag agent, as disclosed herein. The methods may comprise providing instractions to connect the delivery device to one or more of a power source and a supply of gas, for example, connect the console to one or more of a power source and a supply of gas. The methods may comprise providing instructions to load a drag agent cartridge in the delivery device, for example, in the treatment head.Docket No. A2246-7000WO

[0117] In certain embodiments, the methods disclosed herein may comprise providing a drug agent cartridge. In certain embodiments, the methods may comprise providing a supply of gas. In certain embodiments, the methods may comprise providing a power source.

[0118] In certain embodiments, the methods may comprise connecting the delivery device to one or more of a power source and a supply of gas, for example, connecting the console to one or more of a power source and a supply of gas. The methods may comprise selecting the supply of gas, for example, selecting the gas from a noble gas or a combination of noble gases. Exemplary gases include helium and argon. In certain embodiments, the supply of gas may further comprise one or more of nitrogen (N2), oxygen (O2), and water vapor. The methods may comprise loading a drug agent cartridge in the delivery device, for example, in the treatment head. The methods may comprise selecting the drug agent from a list of drug agents known or approved for treatment of the particular medical application. Exemplary drug agents include photosensitizing agents such as riboflavin, methylene blue, toluidine blue, rose Bengal, curcumin, hypericin, phthalocyanines, porphyrins, zinc, nanostructures such as fullerenes or titanium dioxide, or combinations thereof.

[0119] EXAMPLES

[0120] The function and advantages of these and other embodiments can be better understood from the following examples. These examples are intended to be illustrative in nature and are not considered to be limiting the scope of the invention. For instance, even though the examples shown are for treatment of infectious keratitis, keratoconus, and diabetic foot ulcers, the benefits of the systems and methods disclosed herein are broadly applicable to infectious diseases that are challenging to treat with conventional medications. The systems and methods disclosed herein may be effective and safe in treatment of infectious conditions that frequently lead to eye removal or amputations and, in severe cases, life threatening sepsis.

[0121] Example 1: Infectious Keratitis

[0122] The systems and methods disclosed herein may be utilized for treatment of infectious keratitis, an infection of the cornea caused by a bacterial, fungal, parasitic, or viral organism. Infectious keratitis is a leading cause of blindness due to its rapidly progressive nature and, often, resistance to pharmaceutical treatments. These infections often form biofilms in the cornea thatDocket No. A2246-7000WO

[0123] further increase their resistance to pharmaceutical treatment. Therefore, this type of infection often requires alternate treatment strategies beyond purely drug-based approaches.

[0124] Application of an APPJ alone to an infected cornea may provide some therapeutic effect from direct exposure to the RONS in the plasma stream. However, APPJ alone may have significant, counterproductive limitations. For example, certain viruses that cause infectious keratitis, such as herpes simplex, are activated by exposure to UV radiation at wavelengths similar to those emitted by an APPJ. Additionally, the human retina and ocular lens are highly sensitive to UV radiation and may be easily damaged by prolonged exposure to the UV photons in an APPJ. It therefore may be beneficial, when treating ophthalmic conditions with an APPJ, to limit total treatment time and to limit exposure of the eye to UV radiation.

[0125] For treatment of infectious keratitis or a similar microbial, viral, fungal, and / or parasitic infection, the drug agent selected to be paired with the APPJ may be a photosensitizing agent such as riboflavin, methylene blue, toluidine blue, rose Bengal, curcumin, hypericin, phthalocyanines, porphyrins, zinc, nanostructures such as fullerenes or titanium dioxide, or a combination thereof. In particular, the drug agent may be selected to produce a photosensitizing effect, in an amount effective to amplify ROS creation and decrease treatment time, in addition to improving treatment safety by absorbing UV radiation during ROS creation and thereby reducing the UV exposure of sensitive ocular tissues.

[0126] With infectious keratitis, infections can sometimes form in cysts encapsulated in a biofilm. Infectious organisms may also be present in areas of the cornea underneath an intact corneal epithelial layer. In both cases, transport of a conventionally applied drug agent and the reactive species to the infectious organisms is impeded by tight junctions in the biofilm and / or the corneal epithelium.

[0127] Use of the delivery device to produce a mixed stream of APPJ with a photosensitizing drug agent for treatment of infectious keratitis by administration of the mixed stream to ophthalmic tissues is thus envisioned herein. The temporary electroporation effect produced by the APPJ would open tight junctions and allow improved delivery of the drug agent to the cysts and / or cornea. Increased drug agent concentrations at the infection site, in the case where the drug agent is a photosensitizer with strong UV absorption, would put the infectious organism under further increased stress due to additional ROS generation. Thus, administration of the mixed stream of APPJ and the photosensitizer would be expected to provide treatment for infectious keratitis,Docket No. A2246-7000WO

[0128] without significant side effects to the subject. The delivery device disclosed herein would be expected to produce a mixed stream having an effective amount of the APPJ and photosensitizer for treatment of infectious keratitis.

[0129] Infectious keratitis is one example of a rapidly progressive infection, where immediate treatment is required to prevent severe damage, in this case, loss of vision. These ROS amplification effects are especially important to significantly decrease treatment time, protect the ocular tissues from excessive UV exposure, and prevent blindness resulting from the infection.

[0130] Example 2: Keratoconus

[0131] The systems and methods disclosed herein may be utilized for treatment of keratoconus, where loss of organization in the collagen structure of the cornea leads to a loss of biomechanical integrity. Since the eye is pressurized with intraocular fluid, the degradation of corneal strength ultimately leads to the cornea becoming misshapen, irregularly steep, and fundamentally unable to correctly focus light with a resulting loss in vision.

[0132] Comeal cross-linking (CXL) is a conventional treatment for keratoconus. In CXL, a photosensitizing drug agent is applied topically to the surface of the eye and allowed to soak into the cornea for up to 30 minutes. A medical device is then used to apply UV light to the cornea for up to an additional 30 minutes, whereby the UV light is absorbed by the photosensitizing drug agent, leading to ROS generation. The ROS subsequently form cross-linked bonds in the corneal collagen fibers, restoring biomechanical integrity and arresting disease progression.

[0133] Applying a mixture of a photosensitizing drug agent and an APPJ stream may have many benefits for the treatment of keratoconus, similar to the benefits described for the treatment of infectious keratitis, since CXL is also driven by interactions between RONS and the target tissue. Use of the delivery device to produce a mixed stream of APPJ with a photosensitizing drug agent for treatment of keratoconus by administration of the mixed stream to ophthalmic tissues is thus envisioned herein. Amplification of RONS levels can decrease treatment time, thereby improving patient comfort and reducing healthcare costs through lower physician time burden.

[0134] Importantly, the electroporation effects produced by APPJ may preclude the need for removal of the corneal epithelium prior to the treatment. Epithelial removal is a common step in CXL due to the barrier formed by tight junctions in the epithelium, which prevent loading of sufficient drug agent in the cornea to induce the desired effect. Epithelial removal is extremelyDocket No. A2246-7000WO

[0135] painful and is one of the leading causes of CXL complications. Alternately, complex drug agent formulations have been developed to improve delivery through the intact epithelium, but these formulations are more expensive and may require complex multi-part administration. Direct transmission of a stream of plasma-associated RONS, photosensitizing drug agent, and UV light into the corneal stroma through the electroporated epithelial layer represents a much more efficient mechanism for forming collagen cross-links than the conventional methods.

[0136] Thus, administration of the mixed stream of APPJ and the photosensitizer would be expected to provide treatment for keratoconus, without significant side effects to the subject and with reduced pain and discomfort. The delivery device disclosed herein would be expected to produce a mixed stream having an effective amount of the APPJ and photosensitizer for treatment of keratoconus.

[0137] Example 3: Diabetic Foot Ulcer

[0138] The systems and methods disclosed herein may be utilized for treatment of a diabetic foot ulcer. Diabetic foot ulcers are one example of a slow healing wound that is challenging to treat using conventional methods. The formation of diabetic foot ulcers may cause complications during the wound healing process, and diabetic foot ulcers may also be highly susceptible to infection. The effects of the development of diabetic foot ulcers may include delayed wound closure, amputation, frequent surgical interventions, and extended use of antibiotic and / or antifungal treatments.

[0139] Treatment of infections in diabetic foot ulcers may be complicated by the emergence of multi drug resistant organisms. The failure rate of antibiotics in treating infection is significant. Conventional antibiotics are becoming progressively less effective with fewer options available to treat wound infections. There are concerns over antibiotic resistance, limited efficacy due to lack of sustained and effective availability of the bioactive molecule at the site of infection, inability to target a broad spectrum of pathogens, and potential toxicity.

[0140] Applying a mixture of a photosensitizing drug and an APPJ stream may have many benefits for the treatment of diabetic foot ulcers. The plasma stream may disrupt biofilms, enhance tissue permeability, and stimulate wound healing pathways, thereby increasing the efficacy and uptake of the photosensitizing drug agent. Further, the photosensitizing aspect of the drug agent results in a higher concentration of the drag agent at the wound site during treatment. Use of the delivery device to produce a mixed stream of APPJ with a photosensitizing drag agent for treatment ofDocket No. A2246-7000WO

[0141] diabetic foot ulcers by administration of the mixed stream to wound tissue is thus envisioned herein.

[0142] Thus, administration of the mixed stream of APPJ and the photosensitizer would be expected to provide treatment for slow healing wounds, such as diabetic foot ulcers, without significant side effects to the subject. The delivery device disclosed herein would be expected to produce a mixed stream having an effective amount of the APPJ and photosensitizer for treatment of a diabetic foot ulcer and similar slow healing wounds.

[0143] The phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. As used herein, the term “plurality” refers to two or more items or components. The terms “comprising,” “including,” “carrying,” “having,” “containing,” and “involving,” whether in the written description or the claims, are open-ended terms, i.e., to mean “including but not limited to.” Thus, the use of such terms is meant to encompass the items listed thereafter, and equivalents thereof, as well as additional items. Only the transitional phrases “consisting of’ and “consisting essentially of,” are closed or semi-closed phrases, respectively, with respect to the claims. Use of ordinal terms such as “first,” “second,” “third,” and the like in the claims does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element from another having a same name (but for the ordinal term).

[0144] Having thus described several aspects of at least one embodiment, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Any feature described in any embodiment may be included in or substituted for any feature of any other embodiment. Such alterations, modifications, and improvements are intended to be part of this disclosure and are intended to be within the scope. Accordingly, the foregoing description and drawings are by way of example only.

[0145] Those skilled in the art should appreciate that the parameters and configurations described herein are exemplary and that actual parameters and / or configurations will depend on the specific application in which the disclosed methods and materials are used. Those skilled in the art should also recognize or be able to ascertain, using no more than routine experimentation, equivalents to the specific embodiments disclosed.

Claims

Docket No. A2246-7000WOCLAIMSWhat is claimed is:

1. A delivery device for topically applying a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent, the delivery device comprising:a console configured to be coupled to a power source and configured to be coupled to a supply of gas;a treatment head configured to receive a drug agent cartridge, the treatment head comprising a plasma generation chamber configured to be fluidly connected to the supply of gas and a mixing chamber fluidly connected to the plasma generation chamber and configured to receive the drug agent from the drug agent cartridge, the plasma generation chamber comprising an anode electrode and a cathode electrode electrically connectable to the power source, the treatment head being configured to direct the mixed stream toward a target tissue; anda spacer attachment removably attachable to the treatment head.

2. The delivery device of claim 1, wherein the treatment head is further configured to receive the removably attachable drug agent cartridge.

3. The delivery device of claim 1, wherein the mixing chamber is positioned upstream of the plasma generation chamber such that the mixing chamber is configured to fluidly connect a flow of gas from the supply of gas with a drug agent received from the drug agent cartridge upstream from the plasma generation chamber.

4. The delivery device of claim 1, wherein the mixing chamber is positioned within the plasma generation chamber, such that the mixing chamber is configured to fluidly connect a flow of gas from the supply of gas with a drug agent received from the drug agent cartridge between the cathode and anode electrodes.Docket No. A2246-7000WO5. The delivery device of claim 1 , wherein the mixing chamber is positioned downstream of the plasma generation chamber and is configured to be positioned downstream of the drug agent cartridge.

6. The delivery device of claim 1, wherein one or both of the anode electrode and the cathode electrode comprise a ring electrode positioned around the plasma generation chamber.

7. The delivery device of claim 6, wherein the cathode electrode comprises a ring electrode positioned around the plasma generation chamber and the anode electrode comprises a rod electrode positioned within the plasma generation chamber.

8. The delivery device of claim 6, wherein the anode electrode comprises a ring electrode positioned around the plasma generation chamber and the cathode electrode comprises a rod electrode positioned within the plasma generation chamber.

9. The delivery device of claim 1, further comprising a source of ultraviolet light.

10. The delivery device of claim 1, wherein the spacer attachment comprises one or more boundary walls that maintain a substantially constant cross-sectional area of the mixed stream while being directed toward the target tissue.

11. The delivery device of claim 1, wherein the spacer attachment comprises one or more inwardly angled boundary walls that gradually reduce a cross-sectional area of the mixed stream while being directed toward the target tissue.

12. The delivery device of claim 1, wherein an opening at a distal end of the spacer attachment is substantially unobstructed.

13. The delivery device of claim 1, wherein a cross-section of a distal end of the spacer attachment comprises a mechanical reticle.Docket No. A2246-7000WO14. The delivery device of claim 1 , wherein a distal end of the spacer attachment comprises a membrane.

15. The delivery device of claim 14, wherein the membrane is configured to be loaded with a drug or biological agent.

16. The delivery device of claim 1, wherein the spacer attachment comprises an electrical connection configured to maintain a voltage potential on a lateral and / or distal surface of the spacer attachment.

17. A delivery device for topically applying a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent, the delivery device comprising:a console configured to be coupled to a power source and configured to be coupled to a supply of gas, the console being electrically connected to a control system configured to control delivery of the mixed stream in an amount effective to produce a therapeutic effect at a target tissue; anda treatment head configured to receive a drug agent cartridge, the treatment head comprising a plasma generation chamber configured to be fluidly connected to the supply of gas and a mixing chamber fluidly connected to the plasma generation chamber and configured to receive the drug agent from the drug agent cartridge, the plasma generation chamber comprising an anode electrode and a cathode electrode electrically connectable to the power source, the treatment head being configured to direct the mixed stream toward a target tissue.

18. The delivery device of claim 17, wherein the treatment head further comprises a video camera system configured to capture visual images of a treatment zone.

19. The delivery device of claim 18, wherein the control system is programmed to execute an algorithm that identifies one or more areas of the target tissue that require treatment responsive to the visual images of the treatment zone.Docket No. A2246-7000WO20. A delivery device for applying a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent, comprising:a console configured to be coupled to a power source and configured to be coupled to a supply of gas;a handpiece configured to receive a drug agent cartridge, the handpiece comprising a mixing chamber configured to be fluidly connected to the supply of gas and configured to receive the drug agent from the drug agent cartridge, and a connector fluidly connected to the mixing chamber;and an elongate catheter having an inner lumen fluidly connected to the connector and configured to receive a mixture of the gas and the drug agent from the mixing chamber, the elongate catheter comprising:a plasma generation chamber downstream from the inner lumen;an anode ring electrode and a cathode ring electrode electrically connectable to the power source, the anode and cathode ring electrodes positioned around the plasma generation chamber; anda biocompatible sheath encapsulating the inner lumen and the anode and cathode ring electrodes.

21. The delivery device of claim 20, wherein the biocompatible sheath comprises an expandable balloon.

22. The delivery device of claim 20, wherein a distal end of the elongate catheter is dimensioned to allow delivery of the elongate catheter over a guidewire.

23. A method of treating infectious keratitis, keratoconus, or a wound in a subject, comprising administering to a target site of the infectious keratitis, keratoconus, or wound a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent in an amount effective to treat the infectious keratitis, keratoconus, or wound.

24. The method of claim 23, wherein the drug agent is a photosensitizing agent.Docket No. A2246-7000WO25. The method of claim 23, wherein the drug agent is selected from a list of drag agents known or approved for treatment of the infectious keratitis, keratoconus, or wound.

26. The method of claim 23, wherein the drug agent comprises one or more of riboflavin, methylene blue, toluidine blue, rose Bengal, curcumin, hypericin, phthalocyanines, porphyrins, zinc, fullerenes, and titanium dioxide.

27. The method of claim 23, wherein the target site comprises ocular tissue.

28. The method of claim 27, wherein the ocular tissue is affected by infectious keratitis.

29. The method of claim 27, wherein the ocular tissue is affected by keratoconus.

30. The method of claim 23, wherein the target site comprises a wound.

31. The method of claim 30, wherein the wound is a diabetic foot ulcer.

32. A method of administering a mixed stream of an atmospheric pressure plasma jet (APPJ) and a drug agent to a subject, the method comprising:providing a delivery device, the delivery device comprising:a console configured to be coupled to a power source and configured to be coupled to a supply of gas;a treatment head configured to receive a drug agent cartridge, the treatment head comprising a plasma generation chamber configured to be fluidly connected to the supply of gas and a mixing chamber fluidly connected to the plasma generation chamber and configured to receive the drag agent from the drag agent cartridge, the plasma generation chamber comprising an anode electrode and a cathode electrode electrically connectable to the power source, the treatment head being configured to direct the mixed stream toward a target tissue; providing instructions to electrically connect the delivery device to the power source and fluidly connect the delivery device to the supply of gas;Docket No. A2246-7000WOproviding instructions to load the drug agent cartridge into the delivery device; and providing instructions for operation of the delivery device to administer the mixed stream of APPJ and drug agent to a target site of the subject.

33. The method of claim 32, further comprising providing the supply of gas, wherein the supply of gas is selected from a noble gas or a combination of noble gasses.

34. The method of claim 32, further comprising providing the drug agent cartridge.

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