Patent Description:
Needle-free jet injection enables the delivery of a drug without the use of an invasive hypodermic needle, whereby a jet of liquid is accelerated to a high speed. As a result the jet injection provides enough power for the liquid to penetrate the stratum corneum of a subject's skin.

Electroporation is the use of a transmembrane electric field pulse to induce microscopic pathways (pores) in a bio-membrane. These pores are commonly called "electropores. " Their presence allows an agent to pass from one side of the membrane to the other. Thus, electroporation has been used to introduce drugs, DNA or other molecules into multi-cellular tissues, and may prove to be effective for the treatment of certain diseases.

There is a need in the art to provide a means for effectively delivering an agent via jet injection and subsequently being able to electroporate in a single portable, hand-held, selfcontained device.

The invention relates to an electroporation device for use with an agent cartridge defining a volume containing a pre-measured dose of agent therein, the electroporation device comprising:.

In one aspect of the disclosure, an electroporation device for use with an agent cartridge defining a volume containing a pre-measured dose of agent therein. The electroporation device including a housing having an axis extend therethrough, a nozzle at least partially positioned within the housing, a cavity sized to receive at least a portion of the agent cartridge therein and where the nozzle is in fluid communication with the volume of the agent cartridge when the agent cartridge is positioned within the cavity, an array having a plurality of electrodes extending therefrom, a propulsion cartridge configured to operatively engage the agent cartridge when the agent cartridge is positioned within the cavity, and a power supply in electrical communication with the array.

In another aspect of the disclosure, an electroporation device for use with an agent cartridge defining a volume containing a pre-measured dose of agent therein. The electroporation device including a housing defining a cavity sized to receive at least a portion of the agent cartridge therein, a nozzle at least partially positioned within the housing and in fluid communication with the agent cartridge when the cartridge is positioned within the cavity, a propulsion rod positioned at least partially within the housing and movable with respect thereto between an armed position and a deployed position, and where movement of the propulsion rod from the armed position to the deployed position expels at least a portion of the pre-measured dose of agent through the nozzle, a propulsion spring extending between the propulsion rod and the housing, the propulsion spring configured to bias the propulsion rod toward the deployed position, an array having one or more electrodes extending therefrom, a power supply, and a trigger assembly. Where the trigger assembly is adjustable between a first configuration, where the propulsion rod is fixed in the armed position and the power supply is not in electrical communication with the array, and a second position, where the propulsion rod is free to move between the armed and deployed positions and the power supply is in electrical communication with the array.

In still another aspect of the disclosure, an electroporation device including a cartridge defining a volume having a pre-measured dose of agent therein, at least a portion of the volume being sealed off by a plunger, and a jet injection module. The jet injection module including, a first housing defining a cavity sized to receive at least a portion of the cartridge therein, a nozzle at least partially positioned within the housing and in fluid communication with the cartridge when the cartridge is positioned within the cavity, and an array having one or more electrodes extending therefrom, where the array is movable with respect to the first housing between a retracted position, where the electrodes are positioned within the housing, and an extended position, where at least a portion of the electrodes are positioned outside the housing. The jet injection module also including a base assembly being removably couplable to the jet injection module. The base assembly including a propulsion rod positioned at least partially within the housing and movable with respect a thereto between an armed position and a deployed position, and where the propulsion rod is configured to operatively engage the cartridge, a propulsion spring extending between the propulsion rod and the housing, the propulsion spring configured to bias the propulsion rod toward the deployed position, a power supply, and a trigger assembly adjustable between a first configuration, where the propulsion rod is fixed in the armed position and the power supply is not in electrical communication with the array, and a second position, where the propulsion rod is free to move between the armed and deployed positions and the power supply is in electrical communication with the array.

In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and which are shown by way of illustration embodiments that may be practiced. It is to be understood that other embodiments may be utilized and structural or logical changes may be made without departing from the scope of the disclosure. Therefore, the following detailed description is not intended to limit the scope of the present disclosure.

The scope of the present invention is defined in the appended set of claims. The description may contain additional aspects of technical disclosure, which although not part of the claimed invention, are provided to place the invention in a broader technical context and to illustrate possible related technical developments.

The following abbreviated, or shortened, definitions are given to help the understanding of the preferred embodiments of the present disclosure. The abbreviated definitions given here are by no means exhaustive nor are they contradictory to the definitions as understood in the field or dictionary meaning. The abbreviated definitions are given here to supplement or more clearly define the definitions known in the art.

The term "current" as used herein refers to the flow or rate of flow of electric charge in a conductor or medium between two points having a difference in potential, generally expressed in amperes.

The term "ampere" as used herein refers to the standard unit for measuring the strength of an electric current. It is the rate of flow of charge in a conductor or conducting medium of one coulomb per second.

The term "coulomb" as used herein refers to the meter-kilogram-second unit of <NUM> electric charge equal in magnitude to the charge of <NUM> x <NUM> electrons or the charge transported through a conductor by a current of one ampere flowing for one second.

The term "voltage" as used herein refers to the electromotive force, or difference in electrical potential, expressed in volts, which are the practical units of electromotive force or difference in potential between two points in an electric field that requires one joule of work to move a positive charge of one coulomb from the point of lower potential to the point of higher potential.

The term "power" as used herein refers to a source of physical or mechanical force or energy that is at, or can be put to, work, e.g. "electric power, water power.

The term "impedance" as used herein refers to the total opposition offered by an electric circuit to the flow of an alternating current of a single frequency. It is a combination of resistance and reactance and is measured in ohms.

The term "field" as used herein refers to physical quantity specified at points throughout a region of space.

The term "amplitude" as used herein refers to the extreme range of a fluctuating quantity, as an alternating current or the swing of a pendulum, generally measured from the average or mean to the extreme. It is the amount or degree to which a thing extends.

The term "frequency" as used herein refers to the number of periodic oscillations, vibrations, or waves per unit of time. It is usually expressed in hertz (Hz).

"Agent" may mean a polypeptide, a polynucleotide, a small molecule, a macromolecule, or any combination thereof. The agent may be a recombinant nucleic acid sequence encoding an antibody, a fragment thereof, a variant thereof, or a combination thereof, as detailed in <CIT>. The small molecule may be a drug, for example. The drug may be chemically synthesized. "Agent" may mean a composition comprising a polypeptide, a polynucleotide, a small molecule, or any combination thereof. The composition may comprise a recombinant nucleic acid sequence encoding an antibody, a fragment thereof, a variant thereof, or a combination thereof, as detailed in <CIT>. The agent may be formulated in water or a buffer, for example. The buffer may be saline-sodium citrate (SSC) or phosphate-buffered saline (PBS), for example. The ionic content of the buffers may increase conductivity, resulting in increased current flow in the targeted tissue. The concentration of the formulated polynucleotide may be between 1µg and <NUM>/ml. The concentration of the formulated polynucleotide may be 1µg/ml, 10µg/ml, 25µg/ml, 50µg/ml, 100µg/ml, 250µg/ml, 500µg/ml, 750µg/ml, <NUM>/ml, <NUM>/ml, <NUM>/ml, or <NUM>/ml, for example.

A "peptide," "protein," or "polypeptide" as used herein can mean a linked sequence of amino acids and can be natural, synthetic, or a modification or combination of natural and synthetic.

"Polynucleotide" or "oligonucleotide" or "nucleic acid" as used herein means at least two nucleotides covalently linked together. A polynucleotide can be single stranded or double stranded, or can contain portions of both double stranded and single stranded sequence. The polynucleotide can be DNA, both genomic and cDNA, RNA, or a hybrid. The polynucleotide can contain combinations of deoxyribo- and ribo-nucleotides, and combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine, isoguanine, and synthetic or non-naturally occurring nucleotides and nucleosides. Polynucleotides may be a vector. Polynucleotides can be obtained by chemical synthesis methods or by recombinant methods. The polynucleotide may be a siRNA.

"Vector" as used herein means a nucleic acid sequence containing an origin of replication. A vector can be a viral vector, bacteriophage, bacterial artificial chromosome, or yeast artificial chromosome. A vector can be a DNA or RNA vector. A vector can be a self-replicating extrachromosomal vector, and preferably, is a DNA plasmid.

The term "macromolecule" as used herein may refer to nucleic acid sequences, proteins, lipids, microbubbles (e.g. drug-loaded vesicles), and pharmaceuticals, for example.

The term "electroporation," ("EP") as used herein refers to the use of an electric field pulse to induce reversible microscopic pathways (pores) in a bio-membrane; their presence allows agents to pass from one side of the cellular membrane to the other.

The term "skin region" as used herein refers to skin tissue, dermis, epidermis, and intradermic ("ID"), including the region between the stratum corneum and basal layers. The skin region does not include muscle tissue.

The term "needle-free injection" as used herein refers to the injection of an agent into tissue without the use of a needle, for example as a small stream or jet, with such force that the agent pierces the surface of the tissue and enters underlying tissue. In one embodiment, the injector creates a very high-speed jet of liquid that substantially painlessly pierces the tissue. Such needle-free injectors are commercially available and can be used by those having ordinary skill in the art to introduce agents (i.e. by injection) into tissues of a subject.

The term "minimally invasive" as used herein refers to a limited penetration by the needle electrodes of embodiments of an electroporation device, and can include noninvasive electrodes (or nonpenetrating needles). The penetration is to a degree that penetrates through stratum corneum, and preferably enters into the outer most living tissue layer, the stratum granulosum, but does not penetrate the basal layer. The penetration depth is not to exceed <NUM>, and can be a depth ranging from about <NUM> to about <NUM> and in particular from about <NUM> to about <NUM> to break through stratum corneum. This can be accomplished using an electrode that allows penetration through the stratum corneum but avoids deep penetration.

The present disclosure relates to the introduction of a desired agent in a form suitable for direct or indirect electrotransport (e.g., injected) using a needle-free injector into the tissue to be treated, usually by contacting the tissue surface with the injector so as to actuate delivery of a jet of the agent, with sufficient force to cause penetration of the agent into the skin region, for example, to penetrate through the stratum corneum and into dermal layers.

The present disclosure also pertains to a needle-free device, in particular a handheld and portable device, for providing an electric field through an electrode needle array and facilitating the introduction of an agent into cells of a selected tissue in a body, in particular skin. The needle-free device produces a current waveform (e.g., a pulse train) that passes through the electrodes of the electrode needle array in accordance with a programmed sequence and can be monitored and recorded during the procedure. The electrodes are capable of contacting the skin region without substantially penetrating a muscle tissue. <FIG> illustrate a device that can be operable for use in both clinical and commercial environments to administer medical treatment to a patient in the form of jet injection and electroporation. Specifically, <FIG> and <FIG> illustrate a device that can be operable to administer medical treatment to a patient in the form of jet injection. <FIG>, <FIG>, <FIG>, and <FIG> illustrate a combination device that can be operable to administer medical treatment to a patient in the form of jet injection and electroporation. The jet injection module and the electroporation array assembly are coaxially aligned, which decreases the likelihood of error in electroporating the incorrect area. In addition, the electrode array assembly of the present disclosure is retractable, which permits the formation of a bleb/wheal during the jet injection while allowing electroporation immediately upon bleb formation. It may also be possible to use the combination device as an electroporating module, without utilizing the jet injection function, as explained in greater detail below.

As illustrated in <FIG>, the present disclosure includes a needle-free injection system <NUM> including a base assembly <NUM> and a jet injection module <NUM>. The base assembly <NUM> has an upper end <NUM>, a lower end <NUM>, and a longitudinal axis extending therebetween which defines a first axis A. The base assembly <NUM> includes a housing <NUM>, a trigger assembly <NUM>, and a rotational knob <NUM>. The housing <NUM> defines a cavity <NUM> configured to receive a propulsion cartridge <NUM>, as described in greater detail below. The rotational knob <NUM> is positioned at an upper end <NUM> of the base assembly <NUM>. The rotational knob <NUM> has an upper portion <NUM> and a lower portion <NUM> that are configured to be coupled by fasteners <NUM>. Illustrated in <FIG> and <FIG>, the upper and lower portions <NUM>, <NUM> may be coupled to define an interior portion configured to operably couple to the propulsion cartridge <NUM>, as explained in further detail below.

<FIG> and <FIG> illustrate the trigger assembly <NUM> of the base assembly <NUM>. The trigger assembly <NUM> may be positioned anywhere along the length of the base assembly <NUM>. In <FIG>, the trigger assembly <NUM> is positioned at the lower end <NUM> of the housing <NUM>. The trigger assembly <NUM> includes a trigger spring <NUM>, a trigger post <NUM>, and a push button <NUM> configured to actuate the system <NUM>, as explained in further detail below. The push button <NUM> is configured to fit into the housing <NUM> such that the push button <NUM> may travel from a first position, illustrated in <FIG>, to a second, depressed position (e.g., depressed within the housing <NUM>). The direction of travel from the first position to the second position may define a second axis B. In <FIG> and <FIG>, the second axis B is generally perpendicular to the first axis A. The trigger spring <NUM> urges the push button <NUM> toward the first position. The trigger post <NUM> operatively couples the trigger assembly <NUM> to a channel <NUM> of a trigger pin <NUM>, as explained in further detail below. Furthermore, the trigger assembly <NUM> may be in electrical communication with the electroporation components, as also explained in further detail below. The trigger assembly <NUM> may be positioned behind a protective diaphragm (e.g., a plastic and/or gel covering; not illustrated) providing both an ergonomic feel and fluid ingress protection.

As illustrated in <FIG>, <FIG>, the propulsion cartridge <NUM> may include a propulsion rod <NUM>, a propulsion spring <NUM> positioned about at least a portion of the propulsion rod <NUM>, a first housing <NUM>, a second housing <NUM>, and the trigger pin <NUM>. The propulsion cartridge <NUM> may be removably coupled to the base assembly <NUM>. For example, <FIG> shows that a "C" ring <NUM> may be used to removably couple the propulsion cartridge <NUM> to the base assembly <NUM>. In particular, the "C" ring <NUM> may be positioned between the propulsion cartridge <NUM> and the base assembly <NUM> to frictionally couple (e.g., by a compression fitting) the propulsion cartridge <NUM> and the base assembly <NUM>. In other embodiments, the propulsion cartridge <NUM> may be removably coupled to the base assembly <NUM> by fasteners, catches, or by other means as known in the art. In other embodiments, the "C" ring <NUM> may be omitted.

The propulsion spring <NUM> has a pressure profile associated therewith to effectuate the jet injection, as described in greater detail below. The propulsion spring <NUM> may have a spring rate ranging from about <NUM> N/m (<NUM> lbs. ) to about <NUM> N/m (<NUM> lbs. ), from about <NUM> N/m (<NUM> lbs. ) to about <NUM> N/m (<NUM> lbs), and from about <NUM> N/m (<NUM> lbs. ) to about <NUM> N/m (<NUM> lbs. In particular, the spring rate of the propulsion spring <NUM> may be <NUM> N/m (<NUM> lbs. ) (e.g., <NUM> pounds per inch).

While the propulsion cartridge <NUM> is illustrated as being a spring-based system, it is to be understood that the propulsion cartridge <NUM> may include a CO<NUM> based system, a compressed air based system, and the like.

The trigger pin <NUM> is generally tubular shaped and includes a body <NUM>. The body <NUM> has a first portion <NUM>, a second portion <NUM>, a protrusion <NUM> extending from a bottom surface of the second portion <NUM>, and a channel <NUM> extending at least partially therethrough. In the embodiment of <FIG>, the outer diameter of the second portion <NUM> is greater than the outer diameter of the first portion <NUM>. The trigger pin <NUM> is operably coupled to the trigger assembly <NUM> by the trigger post <NUM>. Illustrated in <FIG>, the trigger post <NUM> engages with the channel <NUM> of the trigger pin <NUM> via an aperture <NUM> in the first housing <NUM> of the propulsion cartridge <NUM>. The channel <NUM> can be operably coupled to the trigger post <NUM> using any means known in the art. In particular, the trigger post <NUM> and channel <NUM> are threaded and are configured to be threadably coupled.

Illustrated in <FIG> and <FIG>, a leaf spring <NUM> is cantilevered and has a first end <NUM> and a second end <NUM>. The second end <NUM> has an orifice <NUM> therethrough that is able to receive the protrusion <NUM> of the trigger pin <NUM>. The first end <NUM> of the leaf spring <NUM> is fastened to the first housing <NUM> of the propulsion cartridge <NUM>. The second end <NUM> of the leaf spring <NUM> is free-floating and is positioned adjacent the second portion of the trigger pin <NUM>, opposite the housing aperture <NUM>, to urge the trigger pin <NUM> along the second axis B toward a locked position, as described in greater detail below. In particular, the trigger pin <NUM> is configured to slide in a direction parallel to the second axis B. In one embodiment, the trigger pin <NUM> may slide in a direction coaxial with the second axis B. Therefore, when depressed, the trigger assembly <NUM>, through the trigger post <NUM>, actuates the trigger pin <NUM> in a direction opposite that of the urging direction by the leaf spring <NUM>. In some embodiments, the protrusion of the trigger pin <NUM> operably engages a microswitch <NUM> to begin an EP timing sequence, as described in greater detail below.

A lower end <NUM> of the second housing <NUM> of the propulsion cartridge <NUM> is configured to receive a portion <NUM> of the first housing <NUM> of the propulsion cartridge <NUM> such that the first and second housings <NUM>, <NUM> are axially aligned and further define a third axis C. In <FIG>, the third axis C is coaxial with the first axis A. In other embodiments, the third axis C may be parallel to, but not coaxial with, the first axis A. When coupled together, the housings <NUM>, <NUM> define a substantially cylindrical interior having a passage <NUM> configured for the propulsion rod <NUM> to extend therethrough. At an upper end <NUM>, the second housing <NUM> includes a flange <NUM> and an extension <NUM> of a smaller diameter than the flange <NUM>. The flange <NUM> is shaped to fit within a recess <NUM> at the upper end <NUM> of the housing <NUM> for a firm fitting between the propulsion cartridge <NUM> and the housing <NUM>. The extension <NUM> includes a plurality of slots <NUM> that operably engage the propulsion rod <NUM>, as explained in further detail below. The second housing <NUM> may also include an interior lip <NUM> for providing a first seat for a first end <NUM> of the propulsion spring <NUM>, as illustrated in <FIG>.

The propulsion rod <NUM> includes a lower end <NUM> and an upper end <NUM>. The upper end <NUM> of the propulsion rod <NUM> includes a pin <NUM> such that the propulsion rod <NUM> and the pin <NUM> have a "T" configuration. The pin <NUM> is configured to fit within the slots <NUM> of the extension <NUM> of the second housing <NUM> to prevent rotation of the propulsion rod <NUM>, as explained in further detail below. The lower end <NUM> includes a lip <NUM> and a slot <NUM> which extends through the propulsion rod <NUM> such that the trigger pin <NUM> may extend therethrough. The lip <NUM> provides a second seat for a second end <NUM> of the propulsion spring <NUM>. The slot <NUM>, similar to the trigger pin <NUM>, includes two sections that vary in diameter. Specifically, a large section <NUM> of the slot <NUM> has a diameter that is slightly larger than the outer diameter of the second portion <NUM> of the trigger pin <NUM> so that the second portion <NUM> of the trigger pin <NUM> is able to fit within the large section <NUM> of the slot <NUM>. Likewise, a small section <NUM> of the slot <NUM> has a diameter that is slightly larger than the outer diameter of the first portion <NUM> of the trigger pin <NUM> so that the first portion <NUM> of the trigger pin <NUM> is able to fit within the small section <NUM> of the slot <NUM>. As illustrated in <FIG>, the second portion <NUM> of the trigger pin <NUM> has an outer diameter too large to fit within the small section <NUM> of the slot <NUM>.

The propulsion cartridge <NUM> also includes an arming cam <NUM> and a return spring <NUM>. The arming cam <NUM> and the return spring <NUM> are each configured to be positioned over the extension <NUM> of the second housing <NUM>. The return spring <NUM> may operably engage the rotational knob <NUM> such that the return spring <NUM> urges the rotational knob <NUM> in a clockwise or counterclockwise direction, as explained in greater detail below. The arming cam <NUM> includes helical ramped surfaces <NUM> configured to engage the pin <NUM> of the propulsion rod <NUM>. The arming cam <NUM> may also include at least two extensions <NUM> configured to engage the rotational knob <NUM>, as illustrated in <FIG>. The arming cam <NUM> may include a groove <NUM> for accepting an end of the return spring <NUM>, illustrated in <FIG>. The surface of the flange <NUM> facing the arming cam <NUM> may also have a groove <NUM> for accepting an opposite end of the return spring <NUM>, as illustrated in <FIG>. The grooves of the arming cam <NUM> and the flange <NUM> allow the return spring <NUM> to return the arming cam <NUM>, and consequently the rotational knob <NUM>, to its resting position.

As assembled, the propulsion cartridge <NUM> is positioned within the housing <NUM>, as illustrated in <FIG>. The first housing <NUM> and the second housing <NUM> are coupled to provide the passage <NUM> through which the propulsion rod <NUM> is configured to extend. The propulsion spring <NUM> is positioned about the propulsion rod <NUM>, between the slot <NUM> and the pin <NUM>. In particular, the first end <NUM> of the propulsion spring <NUM> is positioned against the interior lip <NUM> of the first housing <NUM> and the second end <NUM> of the propulsion spring <NUM> is positioned against the lip <NUM> of the propulsion rod <NUM>. The trigger pin <NUM> is positioned in the slot <NUM> such that the propulsion rod <NUM> is capable of moving in a direction parallel to the first axis A. In particular, the propulsion rod <NUM> is generally capable of moving between a relaxed position, as illustrated in <FIG> and <FIG>, and a locked or armed position, as illustrated in <FIG> and <FIG>.

The propulsion spring <NUM> provides a force which urges the propulsion rod <NUM> toward the lower end <NUM> of the base assembly <NUM> or relaxed position so that the large section <NUM> of the slot <NUM> is aligned with the trigger pin <NUM> in a direction parallel with the second axis B. In the relaxed position, illustrated in <FIG>, the first portion <NUM> of the trigger pin <NUM> is positioned within the slot <NUM>. As briefly described above, the leaf spring <NUM> provides a force which urges the trigger pin <NUM> along the axis B such that when the large section <NUM> of the slot <NUM> is presented to the trigger pin <NUM>, the second portion <NUM> of the trigger pin <NUM> moves into the slot <NUM>. As the second portion <NUM> of the trigger pin <NUM> has an outer diameter larger than the small section <NUM> of the slot <NUM>, the propulsion rod <NUM> is locked in place by the urging force of the propulsion spring <NUM>. In this locked position, illustrated in <FIG>, the propulsion spring <NUM> is compressed and is configured to provide an injection force. When the trigger assembly <NUM> is actuated to its second, depressed position, the trigger pin <NUM> is displaced in a direction opposite to the direction of the leaf spring <NUM> force. The displacement of the trigger pin <NUM> moves the second portion <NUM> so that the second portion <NUM> is no longer positioned within the slot <NUM> and first portion <NUM> moves into the slot <NUM>. The outer diameter of the first portion <NUM> of the trigger pin <NUM> is smaller than both the large and the small section <NUM>, <NUM> of the slot <NUM> so that movement of the propulsion rod <NUM> is not restricted. This allows for the propulsion spring <NUM> to relax and move the propulsion rod <NUM> forward to the relaxed position to provide the injection force.

Furthermore, the rotational knob <NUM> is coupled to the extensions <NUM> of the arming cam <NUM>. Accordingly, when the rotational knob <NUM> is rotated, the arming cam <NUM> is also rotated. The arming cam <NUM> allows for the transformation of the rotational force generated by the rotational knob <NUM> to collapse/compress the propulsion spring <NUM>. The arming cam <NUM> and the return spring <NUM> are both positioned about the extension <NUM> of the second housing <NUM>, between the pin <NUM> and the flange <NUM>. The helical ramped surfaces <NUM> of the arming cam <NUM> are positioned against the pin <NUM>, which is positioned within the slots <NUM> of the extension <NUM>. Therefore, when the arming cam <NUM> is rotated by the rotational knob <NUM>, the helical ramped surfaces <NUM> force the pin <NUM> in a direction parallel to the axis A away from the first housing <NUM> (e.g., to the left with respect to <FIG>). However, the propulsion rod <NUM> does not substantially rotate with the arming cam <NUM> and the rotational knob <NUM> because the pin <NUM> is positioned within the slots <NUM> of the extension <NUM>. The propulsion rod <NUM>, being coupled to the pin <NUM>, begins to move away from the trigger pin <NUM> and the propulsion spring <NUM> begins to compress against the interior lip <NUM>. When the rotational knob <NUM> has been rotated about <NUM> degrees, the propulsion rod <NUM> has been moved far enough such that the large section <NUM> of the slot <NUM> is presented to the trigger pin <NUM>, allowing the second portion <NUM> of the trigger pin <NUM> to move into the slot <NUM>, as explained above. The return spring <NUM> may urge the rotational knob <NUM> back toward its original (e.g., at-rest) position after the propulsion rod <NUM> has been moved to the locked position. In other embodiments, the rotational knob <NUM> may need to be rotated more or less than <NUM> degrees to move the propulsion rod <NUM> from the relaxed position to the locked position.

As illustrated in <FIG> and <FIG>, the jet injection module <NUM> includes an injection housing <NUM> having openings <NUM>, <NUM> at both an upper end <NUM> and a lower end <NUM>, respectively. The lower end <NUM> defines an edge <NUM> that surrounds the opening <NUM>. The upper end <NUM> is configured to receive a portion of a cartridge <NUM> and may be removably coupled with the housing <NUM> at the lower end <NUM> of the base assembly <NUM>. As illustrated in <FIG>, the jet injection module <NUM> may include detents <NUM> for coupling to a groove <NUM> positioned in the cavity <NUM> at the lower end <NUM> of the housing <NUM>. The detents <NUM> and groove <NUM> are configured to allow a user to quickly remove and attach the jet injection module <NUM> from the base assembly <NUM>. Furthermore, the injection housing <NUM> may include various sidewalls, ridges, detents, and the like to support the cartridge <NUM> when positioned therein. More specifically, the injection housing <NUM> may include components to help absorb or minimize the pressure forces experienced by the cartridge <NUM>.

As illustrated in <FIG> and <FIG>, the housing <NUM> may also include outer recesses <NUM> extending from the lower end <NUM> to a point on the housing <NUM>, as illustrated in <FIG> and <FIG>. The housing <NUM> may further include interior recesses <NUM> which extend from the outer recesses <NUM>. As illustrated in <FIG>, and <FIG>, the interior recesses <NUM> may be generally smaller than the outer recesses <NUM> and include release pins <NUM> and latch detents <NUM> at each of their respective ends, as explained in further detail below.

The jet injection module <NUM> generally includes a nozzle <NUM> and a mounting boss <NUM> configured to accept the nozzle <NUM>. The mounting boss <NUM> may, for example, be a spider clamp. A volume <NUM> defined by the injection housing <NUM> is configured to removably receive the mounting boss <NUM> therein. The mounting boss <NUM> may be frictionally coupled (e.g., by a compression fitting) to the injection housing <NUM> such that the mounting boss <NUM> is substantially held in place during operation of the system <NUM>, as explained in further detail below. In other embodiments, the mounting boss <NUM> may be removably coupled to the injection housing <NUM> by fasteners, catches, or by other means as known in the art.

The nozzle <NUM> has a proximal end <NUM>, a distal end <NUM>, and a conduit <NUM> extending therebetween such that the proximal end <NUM> and the distal end <NUM> each includes an opening of the conduit <NUM>. The proximal end <NUM> may be beveled so as to be capable of penetrating a septum <NUM> of the cartridge <NUM>, when the cartridge <NUM> is inserted in the jet injection module <NUM>. The distal end <NUM> includes a nozzle tip <NUM> configured to deliver a jet injection to a patient, as described in greater detail below. The nozzle <NUM> may be removably positioned within the mounting boss <NUM> such that the nozzle <NUM> extends axially with the system <NUM> (e.g., a longitudinal axis of the nozzle <NUM> extends parallel with the first axis A). The diameter of the openings and the conduit <NUM> may be designed to any configuration necessary to meet the need of the jet injection cycle to be employed. In one embodiment, the diameter may be about <NUM> to about <NUM> and may deliver a pressure of about <NUM>,<NUM> KPa (<NUM>,<NUM> Psi) to about <NUM>,<NUM> KPa (<NUM>,<NUM> Psi) to the skin surface, as explained in greater detail below.

The nozzle <NUM> is removably coupled to the mounting boss, which is removably coupled to the injection housing <NUM> so that it can be interchanged with nozzles of varying configurations. The nozzle <NUM> can have various tapering and tip <NUM> configurations, thereby allowing a jet stream to be applied to a patient's skin surface in a number of differing patterns. The nozzle <NUM> can also have various internal funneling configurations capable of allowing for the jet stream to have a laminar flow or a turbulent flow. Accordingly, changing the nozzle tip <NUM> may enhance transfection by including things such as, but not limited to, multiple orifice outlets configured to increase distribution of the liquid and coverage of electroporation.

The distance between the surface of the subject's skin and the distal end <NUM> of nozzle <NUM> can vary in according to a number of factors including but not limited to, the viscosity of the agent, the spring rate of the propulsion spring <NUM>, and the diameter of the nozzle tip <NUM>. For example, the nozzle tip <NUM> can be about <NUM> to about <NUM> above the surface of the subject's skin.

The base assembly <NUM>, the jet injection module <NUM>, and the propulsion cartridge may be made of materials known in the art including, but not limited to, plastic (e.g., polycarbonate), ceramic, and stainless steel or other metals.

As illustrated in <FIG> and <FIG>, the system <NUM> can further include an EP array assembly <NUM>. The EP array assembly <NUM> generally includes an array <NUM> having at least two needle electrodes <NUM>, a flex circuit <NUM>, a mounting support slide <NUM>, and an array spring <NUM>. The EP array assembly <NUM> may be removably coupled to and positioned within the volume <NUM> at the lower end <NUM> of the injection housing <NUM>, as explained in greater detail below.

As illustrated in <FIG>, the flex circuit <NUM> includes a base plate <NUM> having a first orifice <NUM> at its center, a circuit extension <NUM>, and electrical contacts <NUM>. The base plate <NUM> is configured to receive and support the array <NUM>. The array <NUM> is positioned on the base plate <NUM> such that the electrodes <NUM> extend in a first direction from the base plate <NUM> (e.g., to the left with respect to <FIG>). The circuit extension <NUM> is configured to electrically couple the array <NUM> and the electrical contacts <NUM>. The circuit extension <NUM> projects from a side <NUM> of the base plate <NUM> in a direction that is generally perpendicular to the first direction (e.g., up with respect to <FIG>) and continues to extend in a second direction from the base plate <NUM>. The second direction is generally opposite the first direction (e.g., to the right with respect to <FIG>).

The mounting support slide <NUM> includes a depression <NUM> configured to receive at least a portion of the base plate <NUM>. In one embodiment, the depression <NUM> may be about half of the width of the base plate <NUM> so that, when assembled, the circuit extension <NUM> projects from the base plate <NUM> from outside of the depression <NUM>. In other embodiments, the depression <NUM> may include a channel (not illustrated) extending to the perimeter of the base plate <NUM>, which is shaped so that the circuit extension <NUM> may be positioned therein. In yet other embodiments, the mounting support slide <NUM> may not include a depression <NUM> and aligns the base plate <NUM> on the mounting support slide <NUM> by other methods.

The mounting support slide <NUM> further includes a second orifice <NUM> positioned in the center of the depression <NUM> and two outrigger extensions <NUM>. The base plate <NUM> is positioned on the mounting support slide <NUM> so that the first orifice <NUM> and the second orifice <NUM> are generally aligned. As illustrated in <FIG>, the outrigger extensions <NUM> are positioned on opposite sides of the mounting support slide <NUM>. The outrigger extensions <NUM> each include a wide portion <NUM> which has a height that is generally equal to the height of the outer recesses <NUM> and a narrow portion <NUM> which has a height that is generally equal to the height of the interior recesses <NUM>. Each outrigger extension <NUM> includes a latch <NUM> at the end of the narrow portion <NUM> that is configured to couple to the latch detents <NUM> positioned at the end of the interior recesses <NUM>.

As assembled, the EP array assembly <NUM> is configured to move axially from a first (e.g., retracted) position to a second (e.g., extended) position within the volume <NUM> of the injection housing <NUM>. In the first position illustrated in <FIG>, the EP array assembly <NUM> is retracted within the injection housing <NUM>. In the second position illustrated in <FIG>, the EP array assembly <NUM> is moved distally (e.g., to the right with respect to <FIG>) from the first position so that the array <NUM> may come into contact with a subject's skin region for electroporation, as explained in greater detail below.

In particular, the array spring <NUM> is inserted into the volume <NUM> of the injection housing <NUM> so that at least a portion of the array spring <NUM> is positioned about mounting boss <NUM>, as illustrated in <FIG>. The flex circuit <NUM> is coupled to the mounting support slide <NUM> so that the first orifice <NUM> and the second orifice <NUM> are aligned. The flex circuit <NUM> and mounting support slide <NUM> assembly may then be positioned within the volume <NUM> of the injection housing <NUM>. Specifically, as illustrated in <FIG>, the wide portions <NUM> of the outrigger extensions <NUM> may be positioned in the interior recesses <NUM> of the injection housing <NUM> and the narrow portions <NUM> may be positioned in the outer recesses <NUM> to orient the mounting support slide <NUM> so that the latches <NUM> of the outrigger extensions <NUM> may couple to the latch detents <NUM>. As illustrated in <FIG>, the array spring <NUM> may be compressed by the mounting support slide <NUM>, after insertion of the outrigger extensions <NUM> into the recesses <NUM>, <NUM>, thereby readying the support slide <NUM> to provide for the array <NUM> deployment force. The latches <NUM> maintain the EP array assembly <NUM> in the retracted position (i.e., the array spring <NUM> is compressed) by the coupling to the latch detents <NUM>, as illustrated by <FIG> and <FIG>. The latch detents <NUM> may be coupled to the trigger assembly <NUM> such that when the trigger assembly <NUM> is actuated, the latch detents <NUM> release the latches <NUM> through a pair of release pins <NUM>. The decoupling between the latches <NUM> and the latch detents <NUM> allows the array spring <NUM> to relax and force the mounting support slide <NUM>, and therefore the flex circuit <NUM>, outward (e.g., to the right with respect to <FIG>) to provide the array <NUM> deployment force for electroporation, as illustrated by <FIG>. The release pins <NUM> may be attached to the propulsion rod <NUM>, as illustrated in <FIG>, and <FIG>. When the trigger assembly <NUM> is actuated, the release pins <NUM> move forward with the propulsion rod <NUM> and engage the latch detents <NUM>, as illustrated in <FIG>. The release pins <NUM> push the latch detents <NUM>, forcing the latch detents <NUM> inward (e.g., toward the first axis A), allowing the array spring <NUM> to expand.

The deployment force of the mounting support slide <NUM> and the flex circuit <NUM> may be determined by the spring rate of the array spring <NUM>. The array spring <NUM> may have a spring rate ranging from about <NUM> N/m (11b. ) to about <NUM> N/m (<NUM> lbs. ), from about <NUM> N/m (<NUM> lbs) to about <NUM> N/m (<NUM> lbs), from about <NUM> N/m (<NUM> lbs. ) to about <NUM> N/m (<NUM> lbs), and may be <NUM> N/m (<NUM> lbs) (e.g., <NUM> pounds per inch). The array spring <NUM> may be changed between deliveries in order to differ between different spring rates depending on the agent and dosage to be delivered. In other embodiments, the system <NUM> may also include a sensor (not illustrated) for determining the force applied to the EP array assembly <NUM> when positioned on a subject by a user. The sensor may be configured to determine the amount of force that is being applied by the user to the system <NUM> on the subject's skin so that the user does not apply too large or too little force. An auditory and/or visual signal (e.g., by an annunciator or an illuminated LED) may indicate if the user is using too large or too little force. Alternatively, the auditory and/or visual signal may indicate when the user is using a correct amount of force.

After actuation (e.g., the array spring <NUM> forcing the mounting support slide <NUM> forward), the EP array assembly <NUM> may be manually rearmed or re-cocked for use by pushing the EP array assembly <NUM> back into the retracted position. In other embodiments, the jet injection module <NUM> may be disposable, where the module <NUM> is ready for use such that the EP array assembly <NUM> is in the locked position prior to the module <NUM> being operably coupled to the base assembly <NUM>.

As briefly mentioned above, the flex circuit <NUM> includes electrical contacts <NUM> to form an electrical connection with a corresponding electrode <NUM> of the array <NUM>. In the illustrated embodiment of <FIG>, the array <NUM> includes two electrical contacts <NUM> each coupling with a respective electrode <NUM>. However, in alternative embodiments, more or fewer electrical contacts <NUM> may be present. For example, a set number of electrical contacts <NUM> may be present to permit the use of different size arrays (not illustrated), each having a different number of electrodes <NUM>. For example, as illustrated in <FIG>, the array <NUM> may include a set of <NUM> electrodes <NUM> (e.g., a <NUM> x <NUM> electrode arrangement with the centermost electrode being omitted) and <NUM> electric contacts <NUM>. In other embodiments, the electrodes <NUM> of array <NUM> can be spaced such that the centermost electrode does not need to be omitted.

The EP array assembly <NUM> is configured to orient the at least two electrodes <NUM> for electroporation of the patient. For example, when more than two electrodes <NUM> are used, the electrodes <NUM> are arranged to be evenly distributed over the array <NUM>, or over the base plate <NUM> to which the electrodes <NUM> are attached, in square, circular, triangular, or other patterns. In another example, the needle electrodes <NUM> are arranged in a square-like arrangement with each adjacent electrode <NUM> spaced apart in approximately the same distance, except for the electrodes <NUM> on the edge of the square array <NUM>. The array <NUM> may include at least two electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes, <NUM> x <NUM> electrodes or greater. In particular, the array <NUM> may include <NUM> x <NUM> electrodes or <NUM> x <NUM> electrodes. Furthermore, each electrode <NUM> may be spaced apart from each adjacent needle electrode <NUM> at a distance of about <NUM> or less, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>. In particular, the electrodes <NUM> may be spaced at a distance of about <NUM> to about <NUM>, or about <NUM>.

The array <NUM> may be formed using stamping or etching methods as known in the art. The electrodes <NUM> are configured to be minimally invasive and are configured to penetrate the epidermal tissue at depths not to exceed <NUM>, at depths ranging from about <NUM> to about <NUM> and particularly at depths ranging from about <NUM> to about <NUM>.

A variety of known electrodes <NUM> capable of delivering an electrical charge may be incorporated into an embodiment of the minimally invasive system <NUM> of the present disclosure. For example, the electrodes <NUM> may be substantially equivalent to a <NUM> gauge hypodermic needle. The at least two electrodes <NUM> of the array <NUM> extend away from the flex circuit base plate <NUM> to define a tip <NUM> having an angled edge <NUM> at a loading end of the electrode <NUM>. As illustrated in <FIG>, a rake angle of the electrodes may be a defined angle between an axial centerline of the electrode <NUM> and the angled edge <NUM> of the electrode <NUM>. For example, the rake angle may any angle between about <NUM> and about <NUM> degrees, between about <NUM> and about <NUM> degrees and can be about <NUM> degrees, about <NUM> degrees, about <NUM> degrees, or about <NUM> degrees. In particular, the rake angle may be <NUM> degrees from the centerline axis of the electrodes <NUM>. As similarly stated above, the electrodes <NUM> are configured to penetrate layers of epidermis tissue between stratum corneum and basal layers, and are configured to deliver an electrical potential from a voltage generator to the epidermis tissue, as explained in further detail below. For example, the electrodes <NUM> may be of a size typically used in connection with minimally invasive intradermal electroporation.

While the illustrated device is illustrated with a plurality of electrodes <NUM> configured to penetrate layers of the epidermis tissue between stratum corneum and basal layers, it is also appreciated that the electrodes may include plate electrodes, microneedles, and both penetrating and non-penetrating needle electrodes configured to extend into various layers of tissue (for example into skeletal muscle tissue).

Each electrode <NUM> may also include a lead (not illustrated) extending from the electrode <NUM> opposite the tip <NUM>. Each lead is in electrical communication with its corresponding electrode <NUM> and passes a current through the electrode <NUM> to produce an electrical interaction proximate the loading end. When the array <NUM> is installed, each electrode <NUM> of the array <NUM> is configured to engage and form an electrical connection with a corresponding electrical contact <NUM> of the flex circuit <NUM>, as explained above.

As illustrated in <FIG>, a pre-filled cartridge <NUM>, briefly mentioned above, is configured to provide a disposable, one-time dose of a select agent. The disposable cartridge <NUM> is configured to be used with the injection module <NUM>, as explained in further detail below. The cartridge <NUM> is substantially cylindrical in shape and is sized so as to be positioned between the nozzle <NUM> of the injection module <NUM> and the propulsion cartridge <NUM> within the housing <NUM> and the injection housing <NUM>, as illustrated in <FIG>, <FIG>, and <FIG>. The cartridge <NUM> includes a body <NUM>. The body <NUM> defines a volume <NUM>, is selectively sealed on a first end <NUM> by a plunger <NUM>, and is selectively sealed on a second end <NUM> by the septum <NUM>. As mentioned above, the septum <NUM> is configured to be punctured by the nozzle <NUM>. It is to be understood that the body <NUM> of the cartridge may be formed from glass, plastic, or other materials.

The cartridge <NUM> also includes the plunger <NUM>, mentioned above, positioned within the volume <NUM> and is moveable axially therewith between a start position, proximate the first end <NUM> of the body <NUM> and illustrated in <FIG>, <FIG>, and an end position, proximate the second end <NUM> of the body <NUM> and illustrated in <FIG>, <FIG>, and <FIG>. The plunger <NUM> is shaped such that it forms a seal within the volume <NUM> of the body <NUM> at a plunger head <NUM>. Movement of the plunger <NUM> from the start position toward the end position is configured to cause the volume <NUM> of the cartridge <NUM> to shrink, thereby forcing any fluid (e.g., the agent) contained therein out of the punctured septum <NUM>.

The needle-free injection system <NUM> may also include an electrical system <NUM>, illustrated in <FIG>, <FIG>, and <FIG>. The electrical system <NUM> generally includes an EP housing <NUM> and an electroporation assembly positioned within a volume defined by the EP housing <NUM>. The electroporation assembly includes, among other things, a controller (not illustrated) having a printed circuit board ("PCB") <NUM>, a waveform logger (not illustrated) in electrical communication with the controller, an electroporation pulse generator/module (not illustrated) in electrical communication with the controller and being configured to deliver an electric pulse, a power supply <NUM> in electrical communication with the electroporation pulse generator/module and configured to send an electrical charge to the pulse generator, and a plurality of electrical leads and contacts <NUM> configured to form an electrical connection with the electrical contacts <NUM> of the flex circuit <NUM>.

The EP housing <NUM> generally includes a first case <NUM>, a second case <NUM>, and a plurality of fasteners <NUM> for coupling the first case <NUM> to the second case <NUM>. As illustrated in <FIG>, the housing <NUM> may include a lower projection <NUM> having a lip <NUM> configured to couple to the first case <NUM> and the second case <NUM>. The first case <NUM> and the second case <NUM> each include a channel <NUM>, <NUM> configured to accept the lip <NUM> of the lower projection <NUM>. The channel <NUM>, <NUM> is positioned at a top side of the first case <NUM> and the second case <NUM> such that when the first case <NUM> and the second case <NUM> are coupled to the housing <NUM>, the EP housing <NUM> extends below the housing <NUM> (e.g., in a direction parallel to the second axis B). After the first case <NUM> and the second case <NUM> are positioned about the lip <NUM>, the fasteners <NUM> may be inserted into openings <NUM> of the second case <NUM> and into threaded couplings (not illustrated) of the first case <NUM> to couple the first case <NUM> to the second case <NUM>.

The EP housing <NUM> also generally includes a contact housing <NUM> and electrical contacts <NUM>, which can be positioned between the first case <NUM> and the second case <NUM>, as illustrated in <FIG>. For example, the contact housing <NUM> may be positioned within a slot <NUM> defined by a space between the first case <NUM> and the second case <NUM>.

In one embodiment, the electrical contacts <NUM> include a support <NUM>. The electrical leads and contacts <NUM> are generally positioned throughout the system <NUM> to allow the various electrical components, as described above and below, to be in electrical/operable communication with one another. For example, the EP array assembly <NUM> and the electroporation pulse module which, as briefly mentioned above, is configured to deliver an electric pulse of selected voltage, current, and duration from the power supply <NUM> to the electrical contacts <NUM> and in turn to the electrodes <NUM> through the electrical contacts <NUM> of the mounting support slide <NUM>.

The controller is configured to receive an input from the user by a user interface, instruct the pulse generator to deliver the pulse of energy to the desired tissue according to the input, and communicate data to the waveform logger according to the pulse of energy delivered, among other things. The controller may include a PCB <NUM>, may be populated with a plurality of electrical and electronic components that provide power and operational control. In some embodiments, the PCB includes a processing unit (e.g., a microprocessor, a microcontroller, or another suitable programmable device), a memory, and a bus. The bus connects various components of the PCB including the memory to the processing unit. The memory includes, for example, a read-only memory ("ROM"), a random access memory ("RAM"), an electrically erasable programmable read-only memory ("EEPROM"), a flash memory, ahard disk, or another suitable magnetic, optical, physical, or electronic memory device. The processing unit is connected to the memory and executes software that is capable of being stored in the RAM (e.g., during execution), the ROM (e.g., on a generally permanent basis), or another non-transitory computer readable medium such as another memory or a disc. Additionally or alternatively, the memory is included in the processing unit. The controller also includes an input/output ("I/O)" unit that includes routines for transferring information between components within the controller and other components of the system <NUM>. The controller is also in electrical communication with a microswitch <NUM>, briefly mentioned above, in electrical communication with the PCB, which provides a master enable signal to initiate a timing sequence to provide a delay between initiation of jet injection and electroporation. For example, the delay between the initiation of jet injection and electroporation may be about <NUM> microseconds. In other embodiments, the delay may be between <NUM> seconds and <NUM> milliseconds. The microswitch <NUM> also generates the timed sequence firing of electric pulse(s) through the EP array assembly <NUM>, as explained in further detail below. The microswitch <NUM> is activated by depressing the push button <NUM> of the trigger assembly <NUM>, explained in greater detail below and illustrated in <FIG>.

Software included in some implementations of the system <NUM> is stored in the memory of the controller. The software includes, for example, firmware, one or more applications, program data, one or more program modules, and other executable instructions. The controller is configured to retrieve from memory and execute, among other things, instructions related to the control processes and methods described above and below. In some embodiments, the controller includes additional, fewer, or different components.

The PCB <NUM> also includes, among other components, a plurality of additional passive and active components such as resistors, capacitors, inductors, integrated circuits, and amplifiers. These components are arranged and connected to provide a plurality of electrical functions to the PCB <NUM> including, among other things, filtering, signal conditioning, or voltage regulation. For descriptive purposes, the PCB <NUM> and the electrical components populated on the PCB <NUM> are collectively referred to as the controller.

The system <NUM> may also be in communication, wirelessly or by other methods as known in the art, with a user interface, briefly mentioned above, to provide usage or status information to the user. The user interface can include, for example, a mobile tablet, a base station/stand, or another type of display. The present disclosure can also include annunciators including but not limited to, for example, a speaker (not illustrated) and LED's (not illustrated) for communication with the user regarding charging status of the battery and other information.

The system <NUM> may be paired with an external base station/stand (not illustrated) that is configured to be in communication with embodiments of the system <NUM> to provide the user with all the informational input advantages of a large, touchscreen interface (i.e., via base station) while still maintaining the flexibility and mobility of an untethered hand-held device (e.g., the needle-free injection system <NUM>). On the base station, the user may be given multiple options for information input, including by typing (on the touchscreen display), or by downloading the information to a flash drive. The base station may also include a step-by-step graphic user interface that simplifies manual data entry. Still further, the base station may include a screen for displaying another graphic user interface that provides, among other things, step-by-step instructions in real-time as the procedure is occurring (i.e., real-time information). In addition to visual aids, the system <NUM> and the base station may include a high fidelity sound system consisting of a CODEC and a speaker to permit complex audio instructions (e.g., more than simple beeps) to be provided to the user.

The power supply <NUM> supplies a nominal AC or DC voltage to the base assembly. The power supply <NUM> may also be configured to supply lower voltages to operate circuits and components within the base assembly <NUM>. In some implementations, the power supply <NUM> includes one or more batteries or battery packs, as illustrated in <FIG>.

In some embodiments, the batteries are replaceable alkaline batteries (for example AA or AAA batteries) or are a type of rechargeable battery. Rechargeable batteries include, for example, lithium-ion, lead-acid, nickel cadmium, nickel metal hydride, etc. Lithium-ion batteries are generally smaller and lighter than conventional lead-acid batteries, which may enable the system <NUM> to be smaller and lighter. In other embodiments, the power supply <NUM> includes supply connections (not illustrated). The supply connections allow the rechargeable batteries to recharge when the base assembly <NUM> is connected to an external electrical supply. For example, the external electrical supply may be an outlet or charger, portable or otherwise. Alternatively, the system <NUM> may include QI standard coils to permit inductive recharging, such that no supply connections are required. If the system <NUM> were to include QI standard coils, the base assembly <NUM> may be placed on a base station for recharging the one or more batteries. As a result of using inductive recharging methods, the system may further inhibit cross-contamination. The QI standard coils may further be in communication with separate communication modules, which may be external to the system <NUM> and/or the base station, and the user interface. For example, the signals may include information, data, serial data, and/or data packets, among other things. The communication module can be coupled to one or more separate communication modules via wires, fiber, and/or wirelessly. Communication via wires and/or fiber can be any appropriate network topology known to those skilled in the art. For example, wired and/or fiber communication may take place over Ethernet. Wireless communication can be any appropriate wireless network topology known to those skilled in the art. For example wireless communication may take place over Wi-Fi, Bluetooth, Zig-Bee, Z-Wave, and/or ANT, among other things.

To preserve power, the system <NUM> may be configured to start a sleep timer after a predetermined time of inactivity (e.g., <NUM> minutes without user interaction with the device). If the sleep timer expires, the device can turn off to preserve power.

The electrical pulses used by the system <NUM> to effect transfection of the cells in the skin tissue (i.e., electroporation) are any known pulse patterns. In particular the pulse pattern can be a square wave pulse. In some embodiments, the electroporation pulse generator can deliver an electric pulse to the desired tissue at voltage levels of about <NUM> V to about <NUM> V, about <NUM> V to about <NUM> V, about <NUM>. 01V to about <NUM> V, about <NUM>. 01V to about <NUM> V, about <NUM>. 01V to about <NUM> V, about <NUM>. 01V to about <NUM> V, about <NUM> V to about <NUM> V, about <NUM> V to about <NUM> V, about <NUM>. 1V to about <NUM> V, about <NUM>. 1V to about <NUM> V, about <NUM>. 1V to about <NUM> V, and about <NUM>. 1V to about <NUM> V. In particular, the electrical pulse may be about <NUM> V to about <NUM> V. In some embodiments, the present disclosure delivers electrical energy that is characterized by an electrical pulse delivering current into the desired tissue at about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, about <NUM> mA to about <NUM> mA, and about <NUM> mA to about <NUM> mA. In particular, the current delivered may be about <NUM> mA to about <NUM> mA, or about <NUM> mA to about <NUM> mA, or <NUM> mA.

The electrical pulses associated with the present disclosure will generally be characterized by the short duration of each pulse, including pulse lengths of about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, and about <NUM> msec to about <NUM> msec. In particular, the electrical pulse length may be about <NUM> msec. The electrical pulses may be followed by a delay in advance of the next pulse. The delay may be about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec pulse, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, about <NUM> msec to about <NUM> msec, and about <NUM> msec to about <NUM> msec. In particular, the delay may be about <NUM> msec. The electric pulses delivered are repeated to deliver a number of pulses for each vaccination. For example, the number of electric pulses delivered may be <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>. In particular, the number of electric pulses may be from <NUM>-<NUM> pulses, or <NUM> or <NUM> pulses.

The cartridge <NUM> may include an identification system to allow the device to verify the contents of the cartridge <NUM> before an injection can occur. Specifically, the cartridge <NUM> may include an embedded RFID tag or other label (not illustrated) readable by the controller when the cartridge <NUM> is installed in the array <NUM>. In such instances, the controller would verify the proper cartridge <NUM> is in place before allowing the injection to take place. In some embodiments (e.g., a standalone EP system), the system <NUM> may function without a cartridge <NUM>.

The present disclosure is configured to increase the immune response by at least about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%,about <NUM>%, about <NUM>%,about <NUM>%, about <NUM>%,about <NUM>%, about <NUM>%, about <NUM>%,about <NUM>%, about <NUM>%,about <NUM>%, about <NUM>%,about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%,about <NUM>%,about <NUM>%, about <NUM>%,about <NUM>%, about <NUM>%,about <NUM>%, or about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% over a naive subject.

In another embodiment, the present disclosure may increase the immune response at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>- fold, at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>-fold, and at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>-fold, at least about <NUM>-fold or at least about <NUM>-fold over a naive subject.

In operation, to treat a subject, the user must first obtain the needle-free injection system <NUM> and at least one of the pre-filled cartridges <NUM> containing the proper agent and dosage. As the system <NUM> powers up, the system <NUM> may perform a number of self-tests, including software tests (e.g., a switching matrix internal test load) to assure the system <NUM> is ready for treatment and verifying the proper cartridge <NUM> is in place before allowing the injection to take place. With the initial setup complete, the user may then insert the cartridge <NUM>. To insert the cartridge <NUM>, the user either obtains a new unused jet injection module <NUM> or can remove the jet injection module <NUM> from the base assembly <NUM> to provide access to the cavity <NUM> at the lower end <NUM> of the housing <NUM> and the opening <NUM> at the upper end <NUM> of the injection housing <NUM> of the injection module <NUM>. The user orients the cartridge <NUM> so that it is coaxial with the injection module <NUM> with the second end <NUM> closest to the beveled proximal end <NUM> of the nozzle <NUM>. The user then axially introduces the cartridge <NUM> into the jet injection module <NUM> until the septum <NUM> is contacted and ultimately pierced by the beveled proximal end <NUM> of the nozzle <NUM>, so that the nozzle <NUM> is in fluid communication with the volume <NUM> of the cartridge <NUM>. In advance of reattaching the injection module <NUM> to the housing <NUM> with the cartridge <NUM>, so the plunger <NUM> is coaxially aligned with the propulsion rod <NUM>, the propulsion rod <NUM> is to be locked in place as detailed below. The user may then begin the jet injection and electroporation procedure.

Prior to operably coupling the injection module <NUM> to housing <NUM>, the user applies a rotational force to the rotational knob <NUM> thereby compressing the propulsion spring <NUM> until the large section <NUM> of the slot <NUM> is moved over the trigger pin <NUM>. As explained above, the leaf spring <NUM> urges the second portion <NUM> of the trigger pin <NUM> into the large section <NUM> of the slot <NUM> to lock the propulsion rod <NUM> in place. The user can then operably couple the injection module <NUM> to the base assembly <NUM>, locate the desired tissue on the subject to receive the jet injection and electroporation, and bring the edge <NUM> of the injection module <NUM> in contact with the skin <NUM> of the subject. Subsequently, the user engages the push button <NUM> which moves the trigger pin <NUM> so that the small section <NUM> is now positioned within the slot <NUM>. No longer being restricted, the propulsion spring <NUM> decompresses so that the propulsion rod <NUM> engages the plunger <NUM>, providing an injection force that is coaxial with the first axis A The plunger head <NUM> moves through the volume <NUM> of the cartridge <NUM>, ultimately deploying the dosage through the nozzle <NUM>, the first orifice <NUM>, and the second orifice <NUM> to the subject's skin <NUM>. Simultaneously, the protrusion <NUM> contacts the microswitch <NUM> that engages the PCB <NUM> to initiate a timing sequence, such that upon completion of the timing sequence (which allows the jet injection to be completed), the electroporation is initiated as prescribed for that particular treatment. As explained above, EP array assembly <NUM> is deployed by the propulsion rod <NUM>. The release pins <NUM> contact the latch detents <NUM>, allowing the EP array assembly <NUM> to deploy. The electrodes <NUM> penetrate the epidermal tissues of the subject's skin <NUM> at depths up to about to about <NUM>, as illustrated in <FIG>. After the timer has ended, the controller emits a signal for the power supply <NUM> to send a current to the contacts <NUM>. The current continues from the contacts <NUM> to the contacts <NUM> of the flex circuit <NUM> and finally to the electrodes <NUM> where electroporation of the subject's skin <NUM> commences according to the predetermined parameters (e.g., the amount of time and number of pulses). As described above, the controller may continue to emit signals to the power supply <NUM> to continue electroporating the subject's skin2.

An annunciator and/or LED's (not illustrated) can indicate the completion of electroporation and the system <NUM> is removed from the subject's skin <NUM>, where the user can remove and replace the jet injection module <NUM> with a new pre-locked module <NUM> or the user can manually rearm or re-cock the system <NUM> for use by pushing the EP array assembly <NUM> back into the retracted position so that the latches <NUM> couple to the latch detents <NUM>.

One of ordinary skill in the art understands that numerous changes and modifications of the EP devices, as explained above, may be made without departing from the scope of the present disclosure.

Example <NUM>. This example compares rat B cell responses generated by the use of influenza pNP (pGX2013) and RSV-F (pGX2303) delivered to the skin by: (<NUM>) Mantoux injection in combination with skin electroporation (SEP); (<NUM>) jet injection in combination with SEP; and (<NUM>) no treatment.

Methods: For the study three groups of rats were immunized: two groups of <NUM> female Wistar rats (<NUM> weeks old) were immunized with pGX2013 and pGX2303 at separate abdominal skin flanks, and a group of <NUM> naive (no treatment) female Wistar rats (<NUM> weeks old) group. Immunizations were performed on day <NUM> and day <NUM>. The treatment was done by injection of 50ug pGx2303/15ug pGX2013in <NUM>µL PBS ID (abdominal flank, separate locations for each plasmid (pGx2303 injected into left flank and pGX2013injected into right flank)) administered either with the ID jet injection device (Biojector® <NUM>, available from Bioject Medical Technologies, Inc, Tigard, OR) or Mantoux injection (using a <NUM> gauge Insulin syringe) and SEP was performed immediately after each injection. Skin electroporation performed using 25V, <NUM> msec per pulse with <NUM> msec delay between pulses (square pulse waveform) and current was capped at <NUM>.

ELISA: Rats were bled by the jugular sampling technique on days <NUM> and <NUM>. Ninety-six (<NUM>)-well flat-bottom plates (Costar <NUM>) were coated overnight at <NUM> with <NUM> ng / ml of Influenza NP (IMR-<NUM>, available from Novus Biologicals) or Hu RSV-F (<NUM>-V08B, available from Sinobiologicals). Plates were washed X4 using an automatic plate wash (wash solution PBS with <NUM>% Tween-<NUM>), and blocked with <NUM>% BSA PBS <NUM>% Tween-<NUM> buffer for two hours at <NUM>. The plates were washed and <NUM> uL aliquots of sera starting at a <NUM>:<NUM> serial dilution in <NUM>% BSA PBS <NUM>% Tween-<NUM> buffer were added in triplicate and incubated for <NUM> hours at <NUM>. The plates were washed and <NUM> uL of goat anti-rat IgG-HRP (Sigma cat# A9037) at a <NUM>: <NUM>,<NUM> dilution was added for <NUM> hour at <NUM>. The plates were washed and developed using a two component (<NUM> ul of each/ well) TMB microwell peroxidase system (Cat# <NUM>-<NUM>-<NUM>, available from Kirkegaard & Perry Laboratories) for <NUM> minutes at room temperature before stop solution (<NUM> ul) was added. OD450 measurements were acquired using Molecular Devices SpectraMax <NUM> and end point titer cutoffs were calculated based on an OD450 reading of twice the PBS background.

Results: As shown in <FIG> and <FIG>, the combination of jet injection plus electroporation resulted in a more rapid immune response being elicited as shown by higher antibody responses at day <NUM> and/or day <NUM> (post-immunization) for both the influenza pNP (pGX2013) and RSV-F (pGX2303) delivered to the skin when compared to the Mantoux injection plus electroporation.

Example <NUM>. A second experiment was performed using new Wistar rats grouped as identified above and according to the immunization, SEP and ELISA methods as set forth in Example <NUM>.

Claim 1:
An electroporation device for use with an agent cartridge defining a volume containing a pre-measured dose of agent therein, the electroporation device comprising:
a housing (<NUM>) having an axis extending therethrough, the housing (<NUM>) further defining a cavity;
a nozzle (<NUM>) at least partially positioned within the housing (<NUM>), wherein the nozzle (<NUM>) includes a nozzle tip (<NUM>) configured to deliver a jet injection of the agent;
wherein the cavity is sized to receive at least a portion of the agent cartridge (<NUM>) therein, and wherein the nozzle (<NUM>) is in fluid communication with the volume of the agent cartridge (<NUM>) when the agent cartridge is positioned within the cavity;
an array (<NUM>) having a plurality of electrodes (<NUM>) extending therefrom;
a propulsion cartridge (<NUM>) configured to operatively engage the agent cartridge (<NUM>) when the agent cartridge (<NUM>) is positioned within the cavity, to expel at least a portion of the pre-measured dose of agent through the nozzle (<NUM>); and
a power supply (<NUM>) in electrical communication with the array (<NUM>) for sending a current to the plurality of electrodes (<NUM>) for electroporating tissue of a subject,
characterized in that the array (<NUM>) is mounted to a support slide (<NUM>) that is axially moveable with respect to the housing (<NUM>) and the nozzle (<NUM>) between a retracted position, where the electrodes (<NUM>) are positioned inside the housing (<NUM>), and an extended position, where at least a portion of the electrodes (<NUM>) are positioned outside the housing (<NUM>),
the propulsion cartridge (<NUM>) includes a propulsion rod (<NUM>) positioned at least partially within the housing (<NUM>) and movable between an armed position and a deployed position with respect to the housing, and wherein the propulsion rod is biased toward the deployed position,
the electroporation device further comprises a trigger assembly (<NUM>), and wherein the trigger assembly (<NUM>) is adjustable between a first position, where the propulsion rod (<NUM>) is fixed in the armed position, and a second position, where the propulsion rod (<NUM>) is adjustable between the armed and deployed positions, and
the array (<NUM>) is not in electrical communication with the power supply when the trigger assembly (<NUM>) is in the first position, and the array (<NUM>) is in electrical communication with the power supply when the trigger assembly (<NUM>) is in the second position.